Publications by authors named "Jeremy Alverson"

12 Publications

  • Page 1 of 1

Cryptic Biosynthesis of the Berkeleypenostatins from Coculture of Extremophilic sp.

J Nat Prod 2021 05 6;84(5):1656-1665. Epub 2021 May 6.

Coculture fermentation of and yielded berkeleypenostatins A-G (-) as well as the previously reported berkeleylactones A-H, the known macrolide A26771B, citrinin, and patulin. As was true with the berkeleylactones, there was no evidence of the berkeleypenostatins in either axenic culture. The structures were deduced from analyses of spectral data, and the absolute configuration of berkeleypenostatin A () was determined by single-crystal X-ray crystallography. Berkeleypenostatins A () and E () inhibited migration of human pancreatic carcinoma cells (HPAF-II). Both compounds were tested by the NCI Developmental Therapeutics Program. In the NCI 60 cell five-dose screen, berkeleypenostatin E () was the more active of the two, with 1-10 μM total growth inhibition (TGI) of all leukemia cell lines, as well as the majority of colon, CNS, melanoma, ovarian, prostate, renal, and breast cancer cell lines.
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http://dx.doi.org/10.1021/acs.jnatprod.1c00248DOI Listing
May 2021

Single Application Cold-Chain Independent Drug Delivery System for Outer Ear Infections.

ACS Biomater Sci Eng 2020 10 3;6(10):5969-5978. Epub 2020 Sep 3.

Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.

Outer ear infections (OE) affect millions of people annually with significant associated healthcare costs. Incorrect administration or non-compliance with the treatment regimen can lead to infection persistence, recurrence, antibiotic resistance, and in severe cases aggravation to malignant otitis externa. Such issues are particularly pertinent for military personnel, patients in nursing homes, the geriatric population, for patients with head or hand tremors and for those with limited or no access to proper healthcare. With the intent of using traditional material science principles to deconvolute material design while increasing relevance and efficacy, we developed a single application, cold-chain independent thixotropic drug delivery system. This can be easily applied into the ear as a liquid, then gels to deliver effective concentrations of antibiotics against bacterial strains commonly associated with OE. The system maintains thixotropic properties over several stress/no stress cycles, shows negligible swelling and temperature dependence, and does not impact the minimum inhibitory concentration or bactericidal effects of relevant antibiotics. Moreover, the thixogels are biocompatible and are well tolerated in the ear. This drug delivery system can readily translate into a user-friendly product, could improve compliance via a single application by the diagnosing health care provider, is expected to effectively treat OE and minimize the development of antibiotic resistance, infection recurrence or exacerbation.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720692PMC
October 2020

Curvature-Dependent Binding of Cytochrome to Cardiolipin.

J Am Chem Soc 2020 11 6;142(46):19532-19539. Epub 2020 Nov 6.

Department of Chemistry and Biochemistry, University of Montana, Missoula, Montana 59812, United States.

Cytochrome binds cardiolipin on the concave surface of the inner mitochondrial membrane, before oxidizing the lipid and initiating the apoptotic pathway. This interaction has been studied , where mimicking the membrane curvature of the binding environment is difficult. Here we report binding to concave, cardiolipin-containing, membrane surfaces and compare findings to convex binding under the same conditions. For binding to the convex outer surface of cardiolipin-containing vesicles, a two-step structural rearrangement is observed with a small rearrangement detectable by Soret circular dichroism (CD) occurring at an exposed lipid-to-protein ratio (LPR) near 10 and partial unfolding detectable by Trp59 fluorescence occurring at an exposed LPR near 23. On the concave inner surface of cardiolipin-containing vesicles, the structural transitions monitored by Soret CD and Trp59 fluorescence are coincident and occur at an exposed LPR near 58. On the concave inner surface of mitochondrial cristae, we estimate the LPR of cardiolipin to cytochrome is between 50 and 100. Thus, cytochrome may have adapted to its native environment so that it can undergo a conformational change that switches on its peroxidase activity when it binds to CL-containing membranes in the cristae early in apoptosis. Our results show that membrane curvature qualitatively affects peripheral protein-lipid interactions and also highlights the disparity between binding studies and their physiological counterparts where cone-shaped lipids, like cardiolipin, are involved.
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http://dx.doi.org/10.1021/jacs.0c07301DOI Listing
November 2020

Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin Resistant .

ACS Infect Dis 2019 11 15;5(11):1896-1906. Epub 2019 Oct 15.

Department of Pharmaceutical Sciences , University of Connecticut , 69 N. Eagleville Road , Storrs , Connecticut 06269 , United States.

The spread of plasmid borne resistance enzymes in clinical isolates is rendering trimethoprim and iclaprim, both inhibitors of dihydrofolate reductase (DHFR), ineffective. Continued exploitation of these targets will require compounds that can broadly inhibit these resistance-conferring isoforms. Using a structure-based approach, we have developed a novel class of ionized nonclassical antifolates (INCAs) that capture the molecular interactions that have been exclusive to classical antifolates. These modifications allow for a greatly expanded spectrum of activity across these pathogenic DHFR isoforms, while maintaining the ability to penetrate the bacterial cell wall. Using biochemical, structural, and computational methods, we are able to optimize these inhibitors to the conserved active sites of the endogenous and trimethoprim resistant DHFR enzymes. Here, we report a series of INCA compounds that exhibit low nanomolar enzymatic activity and potent cellular activity with human selectivity against a panel of clinically relevant TMP resistant (TMP) and methicillin resistant (MRSA) isolates.
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http://dx.doi.org/10.1021/acsinfecdis.9b00222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025792PMC
November 2019

A Controlled Antibiotic Release System for the Development of Single-Application Otitis Externa Therapeutics.

Gels 2017 May 17;3(2). Epub 2017 May 17.

Materials Science Program, University of Montana, Missoula, MT 59812, USA.

Ear infections are a commonly-occurring problem that can affect people of all ages. Treatment of these pathologies usually includes the administration of topical or systemic antibiotics, depending on the location of the infection. In this context, we sought to address the feasibility of a single-application slow-releasing therapeutic formulation of an antibiotic for the treatment of otitis externa. Thixotropic hydrogels, which are gels under static conditions but liquefy when shaken, were tested for their ability to act as drug controlled release systems and inhibit and , the predominant bacterial strains associated with outer ear infections. Our overall proof of concept, including in vitro evaluations reflective of therapeutic ease of administration, formulation stability, cytocompatibility assessment, antibacterial efficacy, and formulation lifespan, indicate that these thixotropic materials have strong potential for development as otic treatment products.
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http://dx.doi.org/10.3390/gels3020019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318594PMC
May 2017

The Berkeleylactones, Antibiotic Macrolides from Fungal Coculture.

J Nat Prod 2017 04 22;80(4):1150-1160. Epub 2017 Mar 22.

Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60607, United States.

A carefully timed coculture fermentation of Penicillium fuscum and P. camembertii/clavigerum yielded eight new 16-membered-ring macrolides, berkeleylactones A-H (1, 4, 6-9, 12, 13), as well as the known antibiotic macrolide A26771B (5), patulin, and citrinin. There was no evidence of the production of the berkeleylactones or A26771B (5) by either fungus when grown as axenic cultures. The structures were deduced from analyses of spectral data, and the absolute configurations of compounds 1 and 9 were determined by single-crystal X-ray crystallography. Berkeleylactone A (1) exhibited the most potent antimicrobial activity of the macrolide series, with low micromolar activity (MIC = 1-2 μg/mL) against four MRSA strains, as well as Bacillus anthracis, Streptococcus pyogenes, Candida albicans, and Candida glabrata. Mode of action studies have shown that, unlike other macrolide antibiotics, berkeleylactone A (1) does not inhibit protein synthesis nor target the ribosome, which suggests a novel mode of action for its antibiotic activity.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467647PMC
April 2017

Pharmaceutical analysis of a novel propargyl-linked antifolate antibiotic in the mouse.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Apr 6;1051:54-59. Epub 2017 Mar 6.

Department of Chemistry and Biochemistry, The University of Montana, Missoula, MT 59812, United States. Electronic address:

Antimicrobial resistance to current antibiotics is a significant public health problem and the need for new antibiotics is a compelling one. We have been developing a new series of antibiotics, propargyl-linked diaminopyrimidines, based on the structure of trimethoprim. To date we have discovered compounds that are effective inhibitors of dihydrofolate reductase (the target of trimethoprim), that are potent antibiotics in vitro against a range of Gram-positive pathogens including methicillin-resistant S. aureus, and that are non-toxic in mammalian cell culture. In this study we report the development of an LC-MS-based protocol for the quantification of our lead antibiotic 37D1-UCP1099 and the application of this assay to follow the concentration of the compound in mouse plasma after intraperitoneal administration. Extraction of 37D1-UCP1099 from mouse plasma was achieved through a liquid-liquid extraction with ethyl acetate. Separation was performed utilizing a reverse-phase C18 column with a ten minute isocratic elution using 47:53 (v/v) 10mM NHHCO:acetonitrile. The lower limit of quantitation for 37D1-UCP1099 was 50ngmL and the assay showed a dynamic range of 50-4000ngmL with good linearity (r≥0.996 for all fits). Intra-day and inter-day precision and accuracy were within 11.3% (%RSD) and 6.6% (%RE) respectably. We have demonstrated that the compound is stable under the assay procedures. The compound was shown to have a mean residence time of 26.2±1.0min and a half-life of 18.2±0.7min after intraperitoneal delivery at 5mgkg. These studies now form the foundation of our work to develop additional analogs of 37D1-UCP1099 with improved pharmacokinetic properties.
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http://dx.doi.org/10.1016/j.jchromb.2017.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635995PMC
April 2017

Charged Nonclassical Antifolates with Activity Against Gram-Positive and Gram-Negative Pathogens.

ACS Med Chem Lett 2016 Jul 5;7(7):692-6. Epub 2016 May 5.

Department of Pharmaceutical Sciences, University of Connecticut , 69 North Eagleville Road, Storrs, Connecticut 06268, United States.

Although classical, negatively charged antifolates such as methotrexate possess high affinity for the dihydrofolate reductase (DHFR) enzyme, they are unable to penetrate the bacterial cell wall, rendering them poor antibacterial agents. Herein, we report a new class of charged propargyl-linked antifolates that capture some of the key contacts common to the classical antifolates while maintaining the ability to passively diffuse across the bacterial cell wall. Eight synthesized compounds exhibit extraordinary potency against Gram-positive S. aureus with limited toxicity against mammalian cells and good metabolic profile. High resolution crystal structures of two of the compounds reveal extensive interactions between the carboxylate and active site residues through a highly organized water network.
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http://dx.doi.org/10.1021/acsmedchemlett.6b00120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948012PMC
July 2016

Crystal structures of Klebsiella pneumoniae dihydrofolate reductase bound to propargyl-linked antifolates reveal features for potency and selectivity.

Antimicrob Agents Chemother 2014 Dec 6;58(12):7484-91. Epub 2014 Oct 6.

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, USA

Resistance to the antibacterial antifolate trimethoprim (TMP) is increasing in members of the family Enterobacteriaceae, driving the design of next-generation antifolates effective against these Gram-negative pathogens. The propargyl-linked antifolates are potent inhibitors of dihydrofolate reductases (DHFR) from several TMP-sensitive and -resistant species, including Klebsiella pneumoniae. Recently, we have determined that these antifolates inhibit the growth of strains of K. pneumoniae, some with MIC values of 1 μg/ml. In order to further the design of potent and selective antifolates against members of the Enterobacteriaceae, we determined the first crystal structures of K. pneumoniae DHFR bound to two of the propargyl-linked antifolates. These structures highlight that interactions with Leu 28, Ile 50, Ile 94, and Leu 54 are necessary for potency; comparison with structures of human DHFR bound to the same inhibitors reveal differences in residues (N64E, P61G, F31L, and V115I) and loop conformations (residues 49 to 53) that may be exploited for selectivity.
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http://dx.doi.org/10.1128/AAC.03555-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249513PMC
December 2014

De novo macrolide-glycolipid macrolactone hybrids: Synthesis, structure and antibiotic activity of carbohydrate-fused macrocycles.

Beilstein J Org Chem 2014 17;10:2215-21. Epub 2014 Sep 17.

Department of Chemistry, University of Connecticut, 55 N. Eagleville Road, U3060, Storrs, CT 06269, USA, +1-860-486-1605 FAX: +1-860-486-2981.

Natural product-like macrocycles were designed as potential antibacterial compounds. The macrocycles featured a D-glucose unit fused into a 12- or 13-member macrolactone. The rings are connected via the C6' and anomeric (C1') positions of the monosaccharide. The new macrocycles/macrolides were characterized by X-ray crystallography. Their structures showed that, in addition to the ester and alkene units, the dihedral angle about the glycosidic linkage (exo-anomeric effect) influenced the overall shape of the molecules. Glycosylation of an available hydroxy group on the macrocycle gave a hybrid macrolide with features common to erythromycin and sophorlipid macrolactone. Weak antibiotic activity (MICs <100 μg/mL) was observed for several of the compounds.
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http://dx.doi.org/10.3762/bjoc.10.229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168945PMC
September 2014

Propargyl-linked antifolates are dual inhibitors of Candida albicans and Candida glabrata.

J Med Chem 2014 Mar 6;57(6):2643-56. Epub 2014 Mar 6.

Department of Pharmaceutical Sciences, University of Connecticut , 69 N. Eagleville Road, Storrs, Connecticut 06269, United States.

Species of Candida, primarily C. albicans and with increasing prevalence, C. glabrata, are responsible for the majority of fungal bloodstream infections that cause morbidity, especially among immune compromised patients. While the development of new antifungal agents that target the essential enzyme, dihydrofolate reductase (DHFR), in both Candida species would be ideal, previous attempts have resulted in antifolates that exhibit inconsistencies between enzyme inhibition and antifungal properties. In this article, we describe the evaluation of pairs of propargyl-linked antifolates that possess similar physicochemical properties but different shapes. All of these compounds are effective at inhibiting the fungal enzymes and the growth of C. glabrata; however, the inhibition of the growth of C. albicans is shape-dependent with extended para-linked compounds proving more effective than compact, meta-linked compounds. Using crystal structures of DHFR from C. albicans and C. glabrata bound to lead compounds, 13 new para-linked compounds designed to inhibit both species were synthesized. Eight of these compounds potently inhibit the growth of both fungal species with three compounds displaying dual MIC values less than 1 μg/mL. Analysis of the active compounds shows that shape and distribution of polar functionality is critical in achieving dual antifungal activity.
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http://dx.doi.org/10.1021/jm401916jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983340PMC
March 2014

Toward new therapeutics for skin and soft tissue infections: propargyl-linked antifolates are potent inhibitors of MRSA and Streptococcus pyogenes.

PLoS One 2012 7;7(2):e29434. Epub 2012 Feb 7.

Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, United States of America.

Hospital- and community-acquired, complicated skin and soft tissue infections, often attributed to Staphylococcus aureus and Streptococcus pyogenes, present a significant health burden that is associated with increased health care costs and mortality. As these two species are difficult to discern on diagnosis and are associated with differential profiles of drug resistance, the development of an efficacious antibacterial agent that targets both organisms is a high priority. Herein we describe a structure-based drug development effort that has produced highly potent inhibitors of dihydrofolate reductase from both species. Optimized propargyl-linked antifolates containing a key pyridyl substituent display antibacterial activity against both methicillin-resistant S. aureus and S. pyogenes at MIC values below 0.1 µg/mL and minimal cytotoxicity against mammalian cells. Further evaluation against a panel of clinical isolates shows good efficacy against a range of important phenotypes such as hospital- and community-acquired strains as well as strains resistant to vancomycin.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029434PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3274548PMC
July 2012