Publications by authors named "Robert A Bonomo"

552 Publications

Association of a geriatric emergency department program with healthcare outcomes among veterans.

J Am Geriatr Soc 2021 Nov 25. Epub 2021 Nov 25.

Medicine Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA.

Background: We aim to describe the outcomes of Geriatric Emergency Room Innovations for Veterans (GERI-VET), the first comprehensive Veterans Affairs Geriatric ED program.

Methods: In this prospective observational cohort study at an urban Veterans Affairs Medical Center ED, participants included Veterans aged 65 years and older treated in the ED from January 7, 2017 to February 29, 2020. Veterans with an Identification of Seniors At Risk (ISAR) score >2 were considered eligible for GERI-VET, receiving geriatric screens and care coordination in addition to standard ED treatment. The control group included GERI-VET eligible Veterans who did not receive GERI-VET care. Propensity score matching was used to compare outcomes in the GERI-VET group (N = 725) and a matched control group (n = 725). Key measures included ED resource utilization, outpatient referrals, ED admission, and 30-day admission.

Results: In the ED, the GERI-VET group received more consults to pharmacy (315 [43.4%] vs. 195 [26.9%], p < 0.001) and social work (399 [55.0%] vs. 132 [18.2%], p < 0.001). The GERI-VET group had higher referral rates to Geriatrics (64 [17.7%] vs. 18 [5.8%], p < 0.001) and Home Based Primary Care (110 [30.4%] vs. 24 [7.8%], p < 0.001). Key outcome measures included lower rates of ED admission (363 [50.1%] vs. 417 [n = 57.5%], p = 0.003) and 30-day hospital admission (412 [56.8%] vs. 464 [64.0%], p = 0.004) without increasing ED length of stay (5.4 ± 2.2 vs. 5.4 ± 2.6 h, p = 0.85) or 72-h ED revisits (23 [3.2%] vs. 16 [2.2%], p = 0.25) in the GERI-VET group.

Conclusions: A program designed to screen for geriatric syndromes and coordinate care among at-risk older Veterans was associated with increased multidisciplinary resource utilization and reduced ED and 30-day admissions without increasing ED length of stay or re-visitation.
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http://dx.doi.org/10.1111/jgs.17572DOI Listing
November 2021

Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study.

Lancet Infect Dis 2021 Nov 9. Epub 2021 Nov 9.

Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries.

Methods: In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov, NCT03646227, and is complete.

Findings: Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2-6] vs 2 [0-4] vs 2 [0-4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2-5] vs 1 [0-3] vs 1 [0-2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42-65) for China versus South America, 50% (41-61) for the USA versus China, and 53% (41-66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8-16; 29 of 246) than in the USA (23%, 16-30; 30 of 130) and South America (28%, 20-37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22-10·50) and the USA (aOR 3·34, 1·50-7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70-2·96).

Interpretation: Global CRKP epidemics have important regional differences in patients' baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions.

Funding: The National Institutes of Health.
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http://dx.doi.org/10.1016/S1473-3099(21)00399-6DOI Listing
November 2021

Orthopedic Implant-Associated and Central Venous Catheter-Associated Infections Caused by spp. in the Veterans Affairs Healthcare System from 2000 to 2020.

Surg Infect (Larchmt) 2021 Oct 20. Epub 2021 Oct 20.

Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

A 72-year-old male developed a late-onset infection of an internal fixation device caused by Although often considered contaminants, bacteria from the genus may also be pathogens. We also summarize cases from the Veteran Health Administration (VHA) from which isolates were recovered and review the relevant literature. Using the national VHA database, we identified patients with cultures that grew spp. We also review published clinical reports describing spp. as a cause of infections. Between January 2000 and September 2020, 18 cases had spp. Of those, isolates were regarded as pathogens for seven cases; all involved prosthetic material that was consequently removed. Two patients had internal fixation devices whereas the remaining five were patients with a central venous catheter. For patients with prosthetic material, recovery of spp. from device-related clinical cultures should prompt consideration of device removal when possible.
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http://dx.doi.org/10.1089/sur.2021.133DOI Listing
October 2021

Structural analysis of the boronic acid β-lactamase inhibitor vaborbactam binding to Pseudomonas aeruginosa penicillin-binding protein 3.

PLoS One 2021 15;16(10):e0258359. Epub 2021 Oct 15.

Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, United States of America.

Antimicrobial resistance (AMR) mediated by β-lactamases is the major and leading cause of resistance to penicillins and cephalosporins among Gram-negative bacteria. β-Lactamases, periplasmic enzymes that are widely distributed in the bacterial world, protect penicillin-binding proteins (PBPs), the major cell wall synthesizing enzymes, from inactivation by β-lactam antibiotics. Developing novel PBP inhibitors with a non-β-lactam scaffold could potentially evade this resistance mechanism. Based on the structural similarities between the evolutionary related serine β-lactamases and PBPs, we investigated whether the potent β-lactamase inhibitor, vaborbactam, could also form an acyl-enzyme complex with Pseudomonas aeruginosa PBP3. We found that this cyclic boronate, vaborbactam, inhibited PBP3 (IC50 of 262 μM), and its binding to PBP3 increased the protein thermal stability by about 2°C. Crystallographic analysis of the PBP3:vaborbactam complex reveals that vaborbactam forms a covalent bond with the catalytic S294. The amide moiety of vaborbactam hydrogen bonds with N351 and the backbone oxygen of T487. The carboxyl group of vaborbactam hydrogen bonds with T487, S485, and S349. The thiophene ring and cyclic boronate ring of vaborbactam form hydrophobic interactions, including with V333 and Y503. The active site of the vaborbactam-bound PBP3 harbors the often observed ligand-induced formation of the aromatic wall and hydrophobic bridge, yet the residues involved in this wall and bridge display much higher temperature factors compared to PBP3 structures bound to high-affinity β-lactams. These insights could form the basis for developing more potent novel cyclic boronate-based PBP inhibitors to inhibit these targets and overcome β-lactamases-mediated resistance mechanisms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258359PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519428PMC
November 2021

The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases.

Front Microbiol 2021 21;12:720991. Epub 2021 Sep 21.

Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London, United Kingdom.

Class A β-lactamases are known for being able to rapidly gain broad spectrum catalytic efficiency against most β-lactamase inhibitor combinations as a result of elusively minor point mutations. The evolution in class A β-lactamases occurs through optimisation of their dynamic phenotypes at different timescales. At long-timescales, certain conformations are more catalytically permissive than others while at the short timescales, fine-grained optimisation of free energy barriers can improve efficiency in ligand processing by the active site. Free energy barriers, which define all coordinated movements, depend on the flexibility of the secondary structural elements. The most highly conserved residues in class A β-lactamases are hydrophobic nodes that stabilize the core. To assess how the stable hydrophobic core is linked to the structural dynamics of the active site, we carried out adaptively sampled molecular dynamics (MD) simulations in four representative class A β-lactamases (KPC-2, SME-1, TEM-1, and SHV-1). Using Markov State Models (MSM) and unsupervised deep learning, we show that the dynamics of the hydrophobic nodes is used as a metastable relay of kinetic information within the core and is coupled with the catalytically permissive conformation of the active site environment. Our results collectively demonstrate that the class A enzymes described here, share several important dynamic similarities and the hydrophobic nodes comprise of an informative set of dynamic variables in representative class A β-lactamases.
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http://dx.doi.org/10.3389/fmicb.2021.720991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490755PMC
September 2021

On the Offensive: the Role of Outer Membrane Vesicles in the Successful Dissemination of New Delhi Metallo-β-lactamase (NDM-1).

mBio 2021 Oct 28;12(5):e0183621. Epub 2021 Sep 28.

Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR), Rosario, Argentina.

The emergence and worldwide dissemination of carbapenemase-producing Gram-negative bacteria are a major public health threat. Metallo-β-lactamases (MBLs) represent the largest family of carbapenemases. Regrettably, these resistance determinants are spreading worldwide. Among them, the New Delhi metallo-β-lactamase (NDM-1) is experiencing the fastest and largest geographical spread. NDM-1 β-lactamase is anchored to the bacterial outer membrane, while most MBLs are soluble, periplasmic enzymes. This unique cellular localization favors the selective secretion of active NDM-1 into outer membrane vesicles (OMVs). Here, we advance the idea that NDM-containing vesicles serve as vehicles for the local dissemination of NDM-1. We show that OMVs with NDM-1 can protect a carbapenem-susceptible strain of Escherichia coli upon treatment with meropenem in a Galleria mellonella infection model. Survival curves of G. mellonella revealed that vesicle encapsulation enhances the action of NDM-1, prolonging and favoring bacterial protection against meropenem inside the larva hemolymph. We also demonstrate that E. coli cells expressing NDM-1 protect a susceptible Pseudomonas aeruginosa strain within the larvae in the presence of meropenem. By using E. coli variants engineered to secrete variable amounts of NDM-1, we demonstrate that the protective effect correlates with the amount of NDM-1 secreted into vesicles. We conclude that secretion of NDM-1 into OMVs contributes to the survival of otherwise susceptible nearby bacteria at infection sites. These results disclose that OMVs play a role in the establishment of bacterial communities, in addition to traditional horizontal gene transfer mechanisms. Resistance to carbapenems, last-resort antibiotics, is spreading worldwide, raising great concern. NDM-1 is one of the most potent and widely disseminated carbapenem-hydrolyzing enzymes spread among many bacteria and is secreted to the extracellular medium within outer membrane vesicles. We show that vesicles carrying NDM-1 can protect carbapenem-susceptible strains of E. coli and P. aeruginosa upon treatment with meropenem in a live infection model. These vesicles act as nanoparticles that encapsulate and transport NDM-1, prolonging and favoring its action against meropenem inside a living organism. Secretion of NDM-1 into vesicles contributes to the survival of otherwise susceptible nearby bacteria at infection sites. We propose that vesicles play a role in the establishment of bacterial communities and the dissemination of antibiotic resistance, in addition to traditional horizontal gene transfer mechanisms.
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http://dx.doi.org/10.1128/mBio.01836-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546644PMC
October 2021

Involvement of the Histone-Like Nucleoid Structuring Protein (H-NS) in Natural Transformation.

Pathogens 2021 Aug 26;10(9). Epub 2021 Aug 26.

Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92831-3599, USA.

Most strains are naturally competent. Although some information is available about factors that enhance or reduce the frequency of the transformation of this bacterium, the regulatory elements and mechanisms are barely understood. In this article, we describe studies on the role of the histone-like nucleoid structuring protein, H-NS, in the regulation of the expression of genes related to natural competency and the ability to uptake foreign DNA. The expression levels of the natural transformation-related genes , , , , , , and significantly increased in a Δ derivative of A118. The complementation of the mutant with a recombinant plasmid harboring restored the expression levels of six of these genes ( remained expressed at high levels) to those of the wild-type strain. The transformation frequency of the A118 Δ strain was significantly higher than that of the wild-type. Similar, albeit not identical, there were consequences when was deleted from the hypervirulent AB5075 strain. In the AB5075 complemented strain, the reduction in gene expression in a few cases was not so pronounced that it reached wild-type levels, and the expression of was enhanced further. In conclusion, the expression of all seven transformation-related genes was enhanced after deleting in A118 and AB5075, and these modifications were accompanied by an increase in the cells' transformability. The results highlight a role of H-NS in natural competence.
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http://dx.doi.org/10.3390/pathogens10091083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470039PMC
August 2021

Histone-like nucleoid-structuring protein (H-NS) regulatory role in antibiotic resistance in Acinetobacter baumannii.

Sci Rep 2021 09 16;11(1):18414. Epub 2021 Sep 16.

Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, 800 N State College Blvd, Fullerton, CA, 92831, USA.

In the multidrug resistant (MDR) pathogen Acinetobacter baumannii the global repressor H-NS was shown to modulate the expression of genes involved in pathogenesis and stress response. In addition, H-NS inactivation results in an increased resistance to colistin, and in a hypermotile phenotype an altered stress response. To further contribute to the knowledge of this key transcriptional regulator in A. baumannii behavior, we studied the role of H-NS in antimicrobial resistance. Using two well characterized A. baumannii model strains with distinctive resistance profile and pathogenicity traits (AB5075 and A118), complementary transcriptomic and phenotypic approaches were used to study the role of H-NS in antimicrobial resistance, biofilm and quorum sensing gene expression. An increased expression of genes associated with β-lactam resistance, aminoglycosides, quinolones, chloramphenicol, trimethoprim and sulfonamides resistance in the Δhns mutant background was observed. Genes codifying for efflux pumps were also up-regulated, with the exception of adeFGH. The wild-type transcriptional level was restored in the complemented strain. In addition, the expression of biofilm related genes and biofilm production was lowered when the transcriptional repressor was absent. The quorum network genes aidA, abaI, kar and fadD were up-regulated in Δhns mutant strains. Overall, our results showed the complexity and scope of the regulatory network control by H-NS (genes involved in antibiotic resistance and persistence). These observations brings us one step closer to understanding the regulatory role of hns to combat A. baumannii infections.
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http://dx.doi.org/10.1038/s41598-021-98101-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446060PMC
September 2021

Effect of Serum Albumin, a Component of Human Pleural Fluid, on Transcriptional and Phenotypic Changes on Acinetobacter baumannii A118.

Curr Microbiol 2021 Nov 14;78(11):3829-3834. Epub 2021 Sep 14.

Department of Biological Science, Center for Applied Biotechnology Studies, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA, USA.

Acinetobacter baumannii is a multidrug-resistant pathogen that causes numerous infections associated with high mortality rates. Exposure to human body fluids, such as human pleural fluid (HPF) and human serum, modulates gene expression in A. baumannii, leading to changes in its pathogenic behavior. Diverse degrees of effects at the transcriptional level were observed in susceptible and carbapenem-resistant strains. The transcriptional analysis of AB5075, a hyper-virulent and extensively drug-resistant strain showed changes in genes associated with quorum sensing, quorum quenching, fatty acids metabolism, and high-efficient iron uptake systems. In addition, the distinctive role of human serum albumin (HSA) as a critical component of HPF was evidenced. In the present work, we used model strain to analyze more deeply into the contribution of HSA in triggering A. baumannii's response. By qRT-PCR analysis, changes in the expression level of genes associated with quorum sensing, biofilm formation, and phenylacetic acid pathway were observed. Phenotypic approaches confirmed the transcriptional response. HSA, a predominant component of HPF, can modulate the expression and behavior of genes not only in a hyper-virulent and extensively drug-resistant A. baumannii model, but also in other strains with a different degree of susceptibility and pathogenicity.
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http://dx.doi.org/10.1007/s00284-021-02649-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557393PMC
November 2021

A Microbiome-Driven Approach to Combating Depression During the COVID-19 Pandemic.

Front Nutr 2021 24;8:672390. Epub 2021 Aug 24.

Integrated Microbiome Core, Department of Dermatology, Case Western Reserve University, Cleveland, OH, United States.

The significant stressors brought about and exacerbated by COVID-19 are associated with startling surges in mental health illnesses, specifically those related to depressive disorders. Given the huge impact of depression on society, and an incomplete understanding of impactful therapeutics, we have examined the current literature surrounding the microbiome and gut-brain axis to advance a potential complementary approach to address depression and depressive disorders that have increased during the COVID-19 pandemic. While we understand that the impact of the human gut microbiome on emotional health is a newly emerging field and more research needs to be conducted, the current evidence is extremely promising and suggests at least part of the answer to understanding depression in more depth may lie within the microbiome. As a result of these findings, we propose that a microbiome-based holistic approach, which involves carefully annotating the microbiome and potential modification through diet, probiotics, and lifestyle changes, may address depression. This paper's primary purpose is to shed light on the link between the gut microbiome and depression, including the gut-brain axis and propose a holistic approach to microbiome modification, with the ultimate goal of assisting individuals to manage their battle with depression through diet, probiotics, and lifestyle changes, in addition to offering a semblance of hope during these challenging times.
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http://dx.doi.org/10.3389/fnut.2021.672390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421528PMC
August 2021

Molecular Diagnosis of SARS-CoV-2: Assessing and Interpreting Nucleic Acid and Antigen Tests.

Pathog Immun 2021 19;6(1):135-156. Epub 2021 Jul 19.

Cleveland Clinic, Cleveland, Ohio.

In this review, we summarize the current status of nucleic acid and antigen testing required for diagnosing SARS-CoV-2 infection and COVID-19 disease. Nucleic acid amplification (NAAT) and antigen-detection (Ag) tests occupy a critically important frontline of defense against SARS-CoV-2 in clinical and public health settings. In early stages of this outbreak, we observed that identifying the causative agent of a new illness of unknown origin was greatly accelerated by characterizing the nucleic acid signature of the novel coronavirus. Results from nucleic acid sequencing led to the development of highly sensitive RT-PCR testing for use in clinical settings and to informing best practices for patient care, and in public health settings to the development of strategies for protecting populations. As the current COVID-19 pandemic has evolved, we have seen how NAAT performance has been used to guide and optimize specimen collection, inform patient triage decisions, reveal unexpected clinical symptoms, clarify risks of transmission within patient care facilities, and guide appropriate treatment strategies. For public health settings during the earliest stages of the pandemic, NAATs served as the only tool available for studying the epidemiology of this new disease by identifying infected individuals, studying transmission patterns, modeling population impacts, and enabling disease control organizations and governments to make challenging disease mitigation recommendations to protect the expanding breadth of populations at risk. With time, the nucleic acid signature has provided the information necessary to understand SARS-CoV-2 protein expression for further development of antigen-based point-of-care (POC) diagnostic tests. The advent of massive parallel sequencing (ie, next generation sequencing) has afforded the characterization of this novel pathogen, informed the sequences best adapted for RT-PCR assays, guided vaccine production, and is currently used for tracking and monitoring SARS-CoV-2 variants.
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http://dx.doi.org/10.20411/pai.v6i1.422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360705PMC
July 2021

Interaction of with Human Serum Albumin: Does the Host Determine the Outcome?

Antibiotics (Basel) 2021 Jul 8;10(7). Epub 2021 Jul 8.

Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92831-3599, USA.

has become a serious threat to human health due to its extreme antibiotic resistance, environmental persistence, and capacity to survive within the host. Two strains, A118 and AB5075, commonly used as model systems, and three carbapenem-resistant strains, which are becoming ever more dangerous due to the multiple drugs they can resist, were exposed to 3.5% human serum albumin (HSA) and human serum (HS) to evaluate their response with respect to antimicrobial resistance, biofilm formation, and quorum sensing, all features responsible for increasing survival and persistence in the environment and human body. Expression levels of antibiotic resistance genes were modified differently when examined in different strains. The gene was upregulated or downregulated in conditions of exposure to 3.5% HSA or HS depending on the strain. Expression levels of and tended to be increased by the presence of HSA and HS, but the effect was not seen in all strains. A118 growing in the presence of HS did not experience increased expression of these genes. Aminoglycoside-modifying enzymes were also expressed at higher or lower levels in the presence of HSA or HS. Still, the response was not uniform; in some cases, expression was enhanced, and in other cases, it was tapered. While AB5075 became more susceptible to rifampicin in the presence of 3.5% HSA or HS, strain A118 did not show any changes. Expression of a gene involved in resistance to rifampicin present in AMA16, was expressed at higher levels when HS was present in the culture medium. HSA and HS reduced biofilm formation and production of N-Acyl Homoserine Lactone, a compound intimately associated with quorum sensing. In conclusion, HSA, the main component of HS, stimulates a variety of adaptative responses in infecting strains.
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http://dx.doi.org/10.3390/antibiotics10070833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300715PMC
July 2021

2-Mercaptomethyl Thiazolidines (MMTZs) Inhibit All Metallo-β-Lactamase Classes by Maintaining a Conserved Binding Mode.

ACS Infect Dis 2021 09 6;7(9):2697-2706. Epub 2021 Aug 6.

School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, U.K.

Metallo-β-lactamase (MBL) production in Gram-negative bacteria is an important contributor to β-lactam antibiotic resistance. Combining β-lactams with β-lactamase inhibitors (BLIs) is a validated route to overcoming resistance, but MBL inhibitors are not available in the clinic. On the basis of zinc utilization and sequence, MBLs are divided into three subclasses, B1, B2, and B3, whose differing active-site architectures hinder development of BLIs capable of "cross-class" MBL inhibition. We previously described 2-mercaptomethyl thiazolidines (MMTZs) as B1 MBL inhibitors (e.g., NDM-1) and here show that inhibition extends to the clinically relevant B2 (Sfh-I) and B3 (L1) enzymes. MMTZs inhibit purified MBLs (e.g., Sfh-I, 0.16 μM) and potentiate β-lactam activity against producer strains. X-ray crystallography reveals that inhibition involves direct interaction of the MMTZ thiol with the mono- or dizinc centers of Sfh-I/L1, respectively. This is further enhanced by sulfur-π interactions with a conserved active site tryptophan. Computational studies reveal that the stereochemistry at chiral centers is critical, showing less potent MMTZ stereoisomers (up to 800-fold) as unable to replicate sulfur-π interactions in Sfh-I, largely through steric constraints in a compact active site. Furthermore, replacement of the thiazolidine sulfur with oxygen (forming an oxazolidine) resulted in less favorable aromatic interactions with B2 MBLs, though the effect is less than that previously observed for the subclass B1 enzyme NDM-1. In the B3 enzyme L1, these effects are offset by additional MMTZ interactions with the protein main chain. MMTZs can therefore inhibit all MBL classes by maintaining conserved binding modes through different routes.
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http://dx.doi.org/10.1021/acsinfecdis.1c00194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435006PMC
September 2021

Monoclonal Antibody Therapy against .

Infect Immun 2021 09 26;89(10):e0016221. Epub 2021 Jul 26.

Los Angeles County and University of Southern Californiagrid.42505.36 Medical Center, Los Angeles, California, USA.

Extremely drug-resistant (XDR) Acinetobacter baumannii is a notorious and frequently encountered pathogen demanding novel therapeutic interventions. An initial monoclonal antibody (MAb), C8, raised against A. baumannii capsule, proved a highly effective treatment against a minority of clinical isolates. To overcome this limitation, we broadened coverage by developing a second antibody for use in a combination regimen. We sought to develop an additional anti-A. baumannii MAb through hybridoma technology by immunizing mice with sublethal inocula of virulent, XDR clinical isolates not bound by MAb C8. We identified a new antibacterial MAb, 65, which bound to strains in a pattern distinct from and complementary to that of MAb C8. MAb 65 enhanced macrophage opsonophagocytosis of targeted strains and markedly improved survival in lethal bacteremic sepsis and aspiration pneumonia murine models of A. baumannii infection. MAb 65 was also synergistic with colistin, substantially enhancing protection compared to monotherapy. Treatment with MAb 65 significantly reduced blood bacterial density, ameliorated cytokine production (interleukin-1β [IL-1β], IL-6, IL-10, and tumor necrosis factor), and sepsis biomarkers. We describe a novel MAb targeting A. baumannii that broadens immunotherapeutic strain coverage, is highly potent and effective, and synergistically improves outcomes in combination with antibiotics.
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http://dx.doi.org/10.1128/IAI.00162-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445169PMC
September 2021

Specific Protein-Membrane Interactions Promote Packaging of Metallo-β-Lactamases into Outer Membrane Vesicles.

Antimicrob Agents Chemother 2021 09 26;65(10):e0050721. Epub 2021 Jul 26.

Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR), Rosario, Argentina.

Outer membrane vesicles (OMVs) act as carriers of bacterial products such as plasmids and resistance determinants, including metallo-β-lactamases. The lipidated, membrane-anchored metallo-β-lactamase NDM-1 can be detected in Gram-negative OMVs. The soluble domain of NDM-1 also forms electrostatic interactions with the membrane. Here, we show that these interactions promote its packaging into OMVs produced by Escherichia coli. We report that favorable electrostatic protein-membrane interactions are also at work in the soluble enzyme IMP-1 while being absent in VIM-2. These interactions correlate with an enhanced incorporation of IMP-1 compared to VIM-2 into OMVs. Disruption of these interactions in NDM-1 and IMP-1 impairs their inclusion into vesicles, confirming their role in defining the protein cargo in OMVs. These results also indicate that packaging of metallo-β-lactamases into vesicles in their active form is a common phenomenon that involves cargo selection based on specific molecular interactions.
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http://dx.doi.org/10.1128/AAC.00507-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448117PMC
September 2021

Risk Factors for and Mechanisms of listin esistance Among nterobacterales: Getting at the CORE of the Issue.

Open Forum Infect Dis 2021 Jul 21;8(7):ofab145. Epub 2021 Apr 21.

Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Background: Despite the recent emergence of plasmid-mediated colistin resistance, the epidemiology and mechanisms of colistin-resistant Enterobacterales (CORE) infections remain poorly understood.

Methods: A case-case-control study was conducted utilizing routine clinical isolates obtained at a single tertiary health system in Ann Arbor, Michigan. Patients with CORE isolates from January 1, 2016, to March 31, 2017, were matched 1:1 with patients with colistin-susceptible Enterobacterales (COSE) and uninfected controls. Multivariable logistic regression was used to compare clinical and microbiologic features of patients with CORE and COSE to controls. A subset of available CORE isolates underwent whole-genome sequencing to identify putative colistin resistance genes.

Results: Of 16 373 tested clinical isolates, 166 (0.99%) were colistin-resistant, representing 103 unique patients. Among 103 CORE isolates, 103 COSE isolates, and 102 uninfected controls, antibiotic exposure in the antecedent 90 days and age >55 years were predictors of both CORE and COSE. Of 33 isolates that underwent whole-genome sequencing, a large variety of mutations associated with colistin resistance were identified, including 4 -1/-1.1 genes and 4 mutations among 9 isolates and 5 and 3 mutations among 8 isolates. Genetic mutations found in species were not associated with known phenotypic colistin resistance.

Conclusions: Increased age and prior antibiotic receipt were associated with increased risk for patients with CORE and for patients with COSE. -1, , and were the predominant colistin resistance-associated mutations identified among and respectively. Mechanisms of colistin resistance among species could not be determined.
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http://dx.doi.org/10.1093/ofid/ofab145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286092PMC
July 2021

Interplay between Meropenem and Human Serum Albumin on Expression of Carbapenem Resistance Genes and Natural Competence in Acinetobacter baumannii.

Antimicrob Agents Chemother 2021 09 19;65(10):e0101921. Epub 2021 Jul 19.

Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, California, USA.

Acinetobacter baumannii A118, a carbapenem-susceptible strain, and AB5075, carbapenem resistant, were cultured in lysogeny broth (LB) or LB with different supplements, such as 3.5% human serum albumin (HSA), human serum (HS), meropenem, or meropenem plus 3.5% HSA. Natural transformation levels were enhanced in A. baumannii A118 and AB5075 cultured in medium supplemented with 3.5% HSA. Addition of meropenem plus 3.5% HSA caused synergistic enhancement of natural transformation in A. baumannii A118. Medium containing 3.5% HSA or meropenem enhanced the expression levels of the competence and type IV pilus-associated genes. The combination meropenem plus 3.5% HSA produced a synergistic enhancement in the expression levels of many of these genes. The addition of HS, which has a high content of HSA, was also an inducer of these genes. Cultures in medium supplemented with HS or 3.5% HSA also affected resistance genes, which were expressed at higher or lower levels depending on the modification required to enhance resistance. The inducing or repressing activity of these modulators also occurred in three more carbapenem-resistant strains tested. An exception was the A. baumannii AMA16 gene, which was repressed in the presence of 3.5% HSA. In conclusion, HSA produces an enhancement of natural transformation and a modification in expression levels of competence genes and antibiotic resistance. Furthermore, when HSA is combined with carbapenems, which may increase the stress response, the expression of genes involved in natural competence is increased in A. baumannii. This process may favor the acquisition of foreign DNA and accelerate evolution.
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http://dx.doi.org/10.1128/AAC.01019-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448116PMC
September 2021

The urgent need for metallo-β-lactamase inhibitors: an unattended global threat.

Lancet Infect Dis 2021 Jul 8. Epub 2021 Jul 8.

Research Service, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, OH, USA; Department of Medicine, Department of Pharmacology, Department of Molecular Biology and Microbiology, Department of Biochemistry, and Case Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Medical Service and Geriatric Research Education and Clinical Center, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, OH, USA; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology, Cleveland, OH, USA. Electronic address:

Due to their superior tolerability and efficacy, β-lactams are the most potent and prescribed class of antibiotics in the clinic. The emergence of resistance to those antibiotics, mainly due to the production of bacterial enzymes called β-lactamases, has been partially solved by the introduction of β-lactamase inhibitors, which restore the activity of otherwise obsolete molecules. This solution is limited because currently available β-lactamase inhibitors only work against serine β-lactamases, whereas metallo-β-lactamases continue to spread, evolve, and confer resistance to all β-lactams, including carbapenems. Furthermore, the increased use of antibiotics to treat secondary bacterial pneumonia in severely sick patients with COVID-19 might exacerbate the problem of antimicrobial resistance. In this Personal View, we summarise the main advances accomplished in this area of research, emphasise the main challenges that need to be solved, and the importance of research on inhibitors for metallo-B-lactamases amidst the current pandemic.
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http://dx.doi.org/10.1016/S1473-3099(20)30868-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266270PMC
July 2021

2-Mercaptomethyl-thiazolidines use conserved aromatic-S interactions to achieve broad-range inhibition of metallo-β-lactamases.

Chem Sci 2021 Jan 5;12(8):2898-2908. Epub 2021 Jan 5.

Laboratorio de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República (UdelaR) Avda. General Flores 2124 CC1157 Montevideo Uruguay

Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all β-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need by prolonging the lifetime of these life-saving drugs. Here we report the synthesis and activity of a series of 2-mercaptomethyl-thiazolidines (MMTZs), designed to replicate MBL interactions with reaction intermediates or hydrolysis products. MMTZs are potent competitive inhibitors of B1 MBLs (, = 0.44 μM NDM-1). Crystal structures of MMTZ complexes reveal similar binding patterns to the most clinically important B1 MBLs (NDM-1, VIM-2 and IMP-1), contrasting with previously studied thiol-based MBL inhibitors, such as bisthiazolidines (BTZs) or captopril stereoisomers, which exhibit lower, more variable potencies and multiple binding modes. MMTZ binding involves thiol coordination to the Zn(ii) site and extensive hydrophobic interactions, burying the inhibitor more deeply within the active site than d/l-captopril. Unexpectedly, MMTZ binding features a thioether-π interaction with a conserved active-site aromatic residue, consistent with their equipotent inhibition and similar binding to multiple MBLs. MMTZs penetrate multiple Enterobacterales, inhibit NDM-1 , and restore carbapenem potency against clinical isolates expressing B1 MBLs. Based on their inhibitory profile and lack of eukaryotic cell toxicity, MMTZs represent a promising scaffold for MBL inhibitor development. These results also suggest sulphur-π interactions can be exploited for general ligand design in medicinal chemistry.
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http://dx.doi.org/10.1039/d0sc05172aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179362PMC
January 2021

"One-Two Punch": Synergistic ß-Lactam Combinations for Mycobacterium abscessus and Target Redundancy in the Inhibition of Peptidoglycan Synthesis Enzymes.

Clin Infect Dis 2021 10;73(8):1532-1536

Department of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics, and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Mycobacterium abscessus subsp. abscessus is one of the most difficult pathogens to treat and its incidence in disease is increasing. Dual β-lactam combinations act synergistically in vitro but are not widely employed in practice. A recent study shows that a combination of imipenem and ceftaroline significantly lowers the minimum inhibitory concentration of clinical isolates, despite both drugs targeting the same peptidoglycan synthesis enzymes. The underlying mechanism of this effect provides a basis for further investigations of dual β-lactam combinations in the treatment of M. abscessus subsp. abscessus, eventually leading to a clinical trial. Furthermore, dual β-lactam strategies may be explored for other difficult mycobacterial infections.
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http://dx.doi.org/10.1093/cid/ciab535DOI Listing
October 2021

Influence of microbiological culture results on antibiotic choices for veterans with hospital-acquired pneumonia and ventilator-associated pneumonia.

Infect Control Hosp Epidemiol 2021 Jun 4:1-8. Epub 2021 Jun 4.

Geriatric Research Education and Clinical Center (GRECC), the VA Northeast Ohio Healthcare System, Cleveland, Ohio.

Objective: We examined the impact of microbiological results from respiratory samples on choice of antibiotic therapy in patients treated for hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP).

Design: Four-year retrospective study.

Setting: Veterans' Health Administration (VHA).

Patients: VHA patients hospitalized with HAP or VAP and with respiratory cultures between October 1, 2014, and September 30, 2018.

Interventions: We compared patients with positive and negative respiratory culture results, assessing changes in antibiotic class and Antibiotic Spectrum Index (ASI) from the day of sample collection (day 0) through day 7.

Results: Between October 1, 2014, and September 30, 2018, we identified 5,086 patients with HAP/VAP: 2,952 with positive culture results and 2,134 with negative culture results. All-cause 30-day mortality was 21% for both groups. The mean time from respiratory sample receipt in the laboratory to final respiratory culture result was longer for those with positive (2.9 ± 1.3 days) compared to negative results (2.5 ± 1.3 days; P < .001). The most common pathogens were Staphylococcus aureus and Pseudomonas aeruginosa. Vancomycin and β-lactam/β-lactamase inhibitors were the most commonly prescribed agents. The decrease in the median ASI from 13 to 8 between days 0 and 6 was similar among patients with positive and negative respiratory cultures. Patients with negative cultures were more likely to be off antibiotics from day 3 onward.

Conclusions: The results of respiratory cultures had only a small influence on antibiotics used during the treatment of HAP/VAP. The decrease in ASI for both groups suggests the integration of antibiotic stewardship principles, including de-escalation, into the care of patients with HAP/VAP.
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http://dx.doi.org/10.1017/ice.2021.186DOI Listing
June 2021

A New Twist: The Combination of Sulbactam/Avibactam Enhances Sulbactam Activity against Carbapenem-Resistant (CRAB) Isolates.

Antibiotics (Basel) 2021 May 13;10(5). Epub 2021 May 13.

Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92831-3599, USA.

An increasing number of untreatable infections are recorded every year. Many studies have focused their efforts on developing new β-lactamase inhibitors to treat multi-drug resistant (MDR) isolates. In the present study, sulbactam/avibactam and sulbactam/relebactam combination were tested against 187 multi-drug resistant (MDR) clinical isolates; both sulbactam/avibactam and sulbactam/relebactam restored sulbactam activity. A decrease ≥2 dilutions in sulbactam MICs was observed in 89% of the isolates when tested in combination with avibactam. Sulbactam/relebactam was able to restore sulbactam susceptibility in 40% of the isolates. In addition, the susceptibility testing using twenty-three AB5075 knockout strains revealed potential sulbactam and/or sulbactam/avibactam target genes. We observed that diazabicyclooctanes (DBOs) β-lactamase inhibitors combined with sulbactam restore sulbactam susceptibility against carbapenem-resistant clinical isolates. However, relebactam was not as effective as avibactam when combined with sulbactam. Exploring novel combinations may offer new options to treat spp. infections, especially for widespread oxacillinases and metallo-β-lactamases (MBLs) producers.
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http://dx.doi.org/10.3390/antibiotics10050577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152955PMC
May 2021

Cryo-EM Determination of Eravacycline-Bound Structures of the Ribosome and the Multidrug Efflux Pump AdeJ of Acinetobacter baumannii.

mBio 2021 06 28;12(3):e0103121. Epub 2021 May 28.

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Antibiotic-resistant strains of the Gram-negative pathogen Acinetobacter baumannii have emerged as a significant global health threat. One successful therapeutic option to treat bacterial infections has been to target the bacterial ribosome. However, in many cases, multidrug efflux pumps within the bacterium recognize and extrude these clinically important antibiotics designed to inhibit the protein synthesis function of the bacterial ribosome. Thus, multidrug efflux within A. baumannii and other highly drug-resistant strains is a major cause of failure of drug-based treatments of infectious diseases. We here report the first structures of the cinetobacter rug fflux (Ade)J pump in the presence of the antibiotic eravacycline, using single-particle cryo-electron microscopy (cryo-EM). We also describe cryo-EM structures of the eravacycline-bound forms of the A. baumannii ribosome, including the 70S, 50S, and 30S forms. Our data indicate that the AdeJ pump primarily uses hydrophobic interactions to bind eravacycline, while the 70S ribosome utilizes electrostatic interactions to bind this drug. Our work here highlights how an antibiotic can bind multiple bacterial targets through different mechanisms and potentially enables drug optimization by taking advantage of these different modes of ligand binding. Acinetobacter baumannii has developed into a highly antibiotic-resistant Gram-negative pathogen. The prevalent AdeJ multidrug efflux pump mediates resistance to different classes of antibiotics known to inhibit the function of the 70S ribosome. Here, we report the first structures of the A. baumannii AdeJ pump, both in the absence and presence of eravacycline. We also describe structures of the A. baumannii ribosome bound by this antibiotic. Our results indicate that AdeJ and the ribosome use very distinct binding modes for drug recognition. Our work will ultimately enable structure-based drug discovery to combat antibiotic-resistant A. baumannii infection.
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http://dx.doi.org/10.1128/mBio.01031-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263017PMC
June 2021

Monoclonal antibody requires immunomodulation for efficacy against Acinetobacter baumannii infection.

J Infect Dis 2021 May 24. Epub 2021 May 24.

Department of Medicine and Department of Molecular Microbiology & Immunology, Keck School of Medicine at the University of Southern California (USC), Los Angeles, CA, 90033, United States.

Monoclonal antibodies (MAbs) are gaining significant momentum as novel therapeutics for infections caused by antibiotic-resistant bacteria. We evaluated the mechanism by which anti-bacterial MAb therapy protects against Acinetobacter baumannii infections. Anti-capsular MAb enhanced macrophage opsonophagocytosis and rescued mice from lethal infections by harnessing complement, macrophages, and neutrophils, yet the degree of bacterial burden did not correlate with survival. Furthermore, MAb therapy reduced pro-inflammatory (IL-1β, IL-6, TNFα) and anti-inflammatory (IL-10) cytokines, which correlated inversely with survival. Although disrupting IL-10 abrogated the survival advantage conferred by the MAb, IL-10-knockout mice treated with MAb could still survive if TNFα production was suppressed directly (via anti-TNFα neutralizing antibody) or indirectly (via macrophage depletion). Thus, even for a MAb that enhances microbial clearance via opsonophagocytosis, clinical efficacy required modulation of pro- and anti-inflammatory cytokines. These findings may inform future MAb development targeting bacteria that trigger the sepsis cascade.
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http://dx.doi.org/10.1093/infdis/jiab265DOI Listing
May 2021

Desirability of Outcome Ranking for the Management of Antimicrobial Therapy (DOOR MAT) Reveals Improvements in the Treatment of Bloodstream Infections Caused by Escherichia coli and Klebsiella pneumoniae in Patients from the Veterans Health Administration.

Clin Infect Dis 2021 10;73(7):1231-1238

Geriatric Research Education and Clinical Center, VA Northeast Ohio Healthcare System, Cleveland, Ohio, USA.

Background: Reductions in the use of broad-spectrum antibiotics is a cornerstone of antimicrobial stewardship. We aim to demonstrate use of the Desirability of Outcome Ranking Approach for the Management of Antimicrobial Therapy (DOOR MAT) to evaluate the treatment of Escherichia coli and Klebsiella pneumoniae bloodstream infections in patients from the Veterans Health Administration (VHA) across a decade.

Methods: Using electronic records, we determined empiric and definitive antibiotic treatments, clinical characteristics, and 30-day mortality of patients with monomicrobial E. coli and K. pneumoniae bloodstream infections hospitalized in VHA medical centers from 2009 to 2018. Focusing on patients treated with parenteral β-lactams and with available antibiotic susceptibility testing results, we applied a range of DOOR MAT scores that reflect the desirability of antibiotic choices according to spectrum and activity against individual isolates. We report trends in resistance and desirability of empiric and definitive antibiotic treatments.

Results: During the 10-year period analyzed, resistance to expanded-spectrum cephalosporins and fluoroquinolones increased in E. coli but not in K. pneumoniae, while resistance to carbapenems and piperacillin-tazobactam remained unchanged. In 6451 cases analyzed, we observed improvements in DOOR MAT scores consistent with deescalation. Improvement in desirability of definitive treatment compared with empiric treatment occurred in 26% of cases, increasing from 16% in 2009 to 34% in 2018. Reductions in overtreatment were sustained and without negative impact on survival.

Conclusions: DOOR MAT provides a framework to assess antibiotic treatment of E. coli and K. pneumoniae bloodstream infections and can be a useful metric in antimicrobial stewardship.
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http://dx.doi.org/10.1093/cid/ciab384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492112PMC
October 2021

A γ-lactam siderophore antibiotic effective against multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp.

Eur J Med Chem 2021 Aug 8;220:113436. Epub 2021 Apr 8.

Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, 44106, USA; Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 44106, USA; Department of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA; Geriatric Research, Education and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, 44106, USA; Departments of Pharmacology, Molecular Biology & Microbiology, And Proteomics & Bioinformatics, Case Western Reserve University, Cleveland, OH, 44106, USA; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, OH, 44106, USA. Electronic address:

Serious infections caused by multidrug-resistant (MDR) organisms (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) present a critical need for innovative drug development. Herein, we describe the preclinical evaluation of YU253911, 2, a novel γ-lactam siderophore antibiotic with potent antimicrobial activity against MDR Gram-negative pathogens. Penicillin-binding protein (PBP) 3 was shown to be a target of 2 using a binding assay with purified P. aeruginosa PBP3. The specific binding interactions with P. aeruginosa were further characterized with a high-resolution (2.0 Å) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 μg/ml at the 6 h time point when administered intravenously or subcutaneously in mice. Employing a meropenem resistant strain of P. aeruginosa, 2 was shown to have dose-dependent efficacy at 50 and 100 mg/kg q6h dosing in a mouse thigh infection model. Lastly, we showed that a novel γ-lactam and β-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone.
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http://dx.doi.org/10.1016/j.ejmech.2021.113436DOI Listing
August 2021

Human Pleural Fluid and Human Serum Albumin Modulate the Behavior of a Hypervirulent and Multidrug-Resistant (MDR) Representative Strain.

Pathogens 2021 Apr 13;10(4). Epub 2021 Apr 13.

Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, Fullerton, CA 92831-3599, USA.

is a nosocomial pathogen capable of causing serious infections associated with high rates of morbidity and mortality. Due to its antimicrobial drug resistance profile, is categorized as an urgent priority pathogen by the Centers for Disease Control and Prevention in the United States and a priority group 1 critical microorganism by the World Health Organization. Understanding how adapts to different host environments may provide critical insights into strategically targeting this pathogen with novel antimicrobial and biological therapeutics. Exposure to human fluids was previously shown to alter the gene expression profile of a highly drug-susceptible strain A118 leading to persistence and survival of this pathogen. Herein, we explore the impact of human pleural fluid (HPF) and human serum albumin (HSA) on the gene expression profile of a highly multi-drug-resistant strain of AB5075. Differential expression was observed for ~30 genes, whose products are involved in quorum sensing, quorum quenching, iron acquisition, fatty acid metabolism, biofilm formation, secretion systems, and type IV pilus formation. Phenotypic and further transcriptomic analysis using quantitative RT-PCR confirmed RNA-seq data and demonstrated a distinctive role of HSA as the molecule involved in 's response.
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http://dx.doi.org/10.3390/pathogens10040471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069197PMC
April 2021

Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa).

Clin Infect Dis 2021 04;72(7):1109-1116

Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: Antimicrobial-resistant infections are commonly encountered in US hospitals and result in significant morbidity and mortality. This guidance document provides recommendations for the treatment of infections caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa).

Methods: A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated common questions regarding the treatment of ESBL-E, CRE, and DTR-P. aeruginosa infections. Based on review of the published literature and clinical experience, the panel provide recommendations and associated rationale for each recommendation. Because of significant differences in the molecular epidemiology of resistance and the availability of specific anti-infective agents globally, this document focuses on treatment of antimicrobial-resistant infections in the United States.

Results: Approaches to empiric treatment selection, duration of therapy, and other management considerations are briefly discussed. The majority of guidance focuses on preferred and alternative treatment recommendations for antimicrobial-resistant infections, assuming that the causative organism has been identified and antibiotic susceptibility testing results are known. Treatment recommendations apply to both adults and children.

Conclusions: The field of antimicrobial resistance is dynamic and rapidly evolving, and the treatment of antimicrobial-resistant infections will continue to challenge clinicians. This guidance document is current as of 17 September 2020. Updates to this guidance document will occur periodically as new data emerge. Furthermore, the panel will expand recommendations to include other problematic gram-negative pathogens in future versions. The most current version of the guidance including the date of publication can be found at www.idsociety.org/practice-guideline/amr-guidance/.
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http://dx.doi.org/10.1093/cid/ciab295DOI Listing
April 2021

Detection of mcr-1 gene in a clinical Escherichia coli strain in North Carolina: first report.

J Glob Antimicrob Resist 2021 06 28;25:154-156. Epub 2021 Mar 28.

Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jgar.2021.03.014DOI Listing
June 2021
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