Publications by authors named "Kate L Seib"

78 Publications

The Lst Sialyltransferase of Neisseria gonorrhoeae Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea.

mBio 2021 03 23;12(2). Epub 2021 Mar 23.

Griffith University, Institute for Glycobiology, Gold Coast, Queensland, Australia

The lipooligosaccharide (LOS) of plays key roles in pathogenesis and is composed of multiple possible glycoforms. These glycoforms are generated by the process of phase variation and by differences in the glycosyltransferase gene content of particular strains. LOS glycoforms of can be terminated with an -acetylneuraminic acid (Neu5Ac), which imparts resistance to the bactericidal activity of serum. However, cannot synthesize the CMP-Neu5Ac required for LOS biosynthesis and must acquire it from the host. In contrast, can synthesize endogenous CMP-Neu5Ac, the donor molecule for Neu5Ac, which is a component of some meningococcal capsule structures. Both species have an almost identical LOS sialyltransferase, Lst, that transfers Neu5Ac from CMP-Neu5Ac to the terminus of LOS. Lst is homologous to the LsgB sialyltransferase of nontypeable (NTHi). Studies in NTHi have demonstrated that LsgB can transfer keto-deoxyoctanoate (KDO) from CMP-KDO to the terminus of LOS in place of Neu5Ac. Here, we show that Lst can also transfer KDO to LOS in place of Neu5Ac in both and Consistent with access to the pool of CMP-KDO in the cytoplasm, we present data indicating that Lst is localized in the cytoplasm. Lst has previously been reported to be localized on the outer membrane. We also demonstrate that KDO is expressed as a terminal LOS structure in samples from infected women and further show that the anti-KDO monoclonal antibody 6E4 can mediate opsonophagocytic killing of Taken together, these studies indicate that KDO expressed on gonococcal LOS represents a new antigen for the development of vaccines against gonorrhea. The emergence of multidrug-resistant strains that are resistant to available antimicrobials is a current health emergency, and no vaccine is available to prevent gonococcal infection. Lipooligosaccharide (LOS) is one of the major virulence factors of The sialic acid -acetylneuraminic acid (Neu5Ac) is present as the terminal glycan on LOS in In this study, we made an unexpected discovery that KDO can be incorporated as the terminal glycan on LOS of by the alpha-2,3-sialyltransferase Lst. We showed that express KDO on LOS and that the KDO-specific monoclonal antibody 6E4 can direct opsonophagocytic killing of These data support further development of KDO-LOS structures as vaccine antigens for the prevention of infection by .
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http://dx.doi.org/10.1128/mBio.03666-20DOI Listing
March 2021

Random Switching of the ModA11 Type III DNA Methyltransferase of Neisseria meningitidis Regulates Entner-Doudoroff Aldolase Expression by a Methylation Change in the eda Promoter Region.

J Mol Biol 2020 10 5;432(21):5835-5842. Epub 2020 Sep 5.

Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia. Electronic address:

Phase-variable DNA methyltransferases (Mods) mediate epigenetic regulation of gene expression. These phase-variable regulons, called phasevarions, have been shown to regulate virulence and immunoevasion in multiple bacterial pathogens. How genome methylation switching mediates gene regulation is unresolved. Neisseria meningitidis remains a major cause of sepsis and meningitis worldwide. Previously, we reported that phase variation (rapid on/off switching) of the meningococcal ModA11 methyltransferase regulates 285 genes. Here we show a bioinformatic analysis that reveals only 26 of the regulated genes have a methylation site located upstream of the gene with potential for direct effect of methylation on transcription. To investigate how methylation changes are "read" to alter gene expression, we used a lacZ gene fusion approach. We showed a 182-nucleotide region upstream of the eda gene (Entner-Doudoroff aldolase) is sufficient to impart methylation-dependent regulation of eda. Site-directed mutagenesis of the 5'-ACGTAGG-3' ModA11 site upstream of the eda gene showed that methylation of this site modulates eda expression. We show that eda is regulated by the PhoB homolog MisR, and that a MisR binding motif overlaps with the ModA11 methylation site. In a MisR mutant, regulation of eda is uncoupled from regulation by ModA11 phasevarion switching. The on/off switching of ModA11 leads to the presence or absence of a N6-methyladenine modification at thousands of sites in the genome. Most of these modifications have no impact on gene regulation. Moreover, the majority of the 285 gene regulon that is controlled by ModA11 phasevarion switching (259/285) are not directly controlled by methylation changes in the promoter region of the regulated genes. Our data are consistent with direct control via methylation of a subset of the regulon, like Eda, whose regulation will trigger secondary effects in expression of many genes.
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http://dx.doi.org/10.1016/j.jmb.2020.08.024DOI Listing
October 2020

Epigenetic Regulation of Virulence and Immunoevasion by Phase-Variable Restriction-Modification Systems in Bacterial Pathogens.

Annu Rev Microbiol 2020 09 20;74:655-671. Epub 2020 Jul 20.

Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia; email:

Human-adapted bacterial pathogens use a mechanism called phase variation to randomly switch the expression of individual genes to generate a phenotypically diverse population to adapt to challenges within and between human hosts. There are increasing reports of restriction-modification systems that exhibit phase-variable expression. The outcome of phase variation of these systems is global changes in DNA methylation. Analysis of phase-variable Type I and Type III restriction-modification systems in multiple human-adapted bacterial pathogens has demonstrated that global changes in methylation regulate the expression of multiple genes. These systems are called phasevarions (phase-variable regulons). Phasevarion switching alters virulence phenotypes and facilitates evasion of host immune responses. This review describes the characteristics of phasevarions and implications for pathogenesis and immune evasion. We present and discuss examples of phasevarion systems in the major human pathogens , , , , , and .
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http://dx.doi.org/10.1146/annurev-micro-090817-062346DOI Listing
September 2020

Moraxella catarrhalis phase-variable loci show differences in expression during conditions relevant to disease.

PLoS One 2020 18;15(6):e0234306. Epub 2020 Jun 18.

Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia.

Moraxella catarrhalis is a human-adapted, opportunistic bacterial pathogen of the respiratory mucosa. Although asymptomatic colonization of the nasopharynx is common, M. catarrhalis can ascend into the middle ear, where it is a prevalent causative agent of otitis media in children, or enter the lower respiratory tract, where it is associated with acute exacerbations of chronic obstructive pulmonary disease in adults. Phase variation is the high frequency, random, reversible switching of gene expression that allows bacteria to adapt to different host microenvironments and evade host defences, and is most commonly mediated by simple DNA sequence repeats. Bioinformatic analysis of five closed M. catarrhalis genomes identified 17 unique simple DNA sequence repeat tracts that were variable between strains, indicating the potential to mediate phase variable expression of the associated genes. Assays designed to assess simple sequence repeat variation under conditions mimicking host infection demonstrated that phase variation of uspA1 (ubiquitous surface protein A1) from high to low expression occurs over 72 hours of biofilm passage, while phase variation of uspA2 (ubiquitous surface protein A2) to high expression variants occurs during repeated exposure to human serum, as measured by mRNA levels. We also identify and confirm the variable expression of two novel phase variable genes encoding a Type III DNA methyltransferase (modO), and a conserved hypothetical permease (MC25239_RS00020). These data reveal the repertoire of phase variable genes mediated by simple sequence repeats in M. catarrhalis and demonstrate that modulation of expression under conditions mimicking human infection is attributed to changes in simple sequence repeat length.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234306PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302503PMC
September 2020

The Vaccine Candidate NHBA Elicits Antibodies That Are Bactericidal, Opsonophagocytic and That Reduce Gonococcal Adherence to Epithelial Cells.

Vaccines (Basel) 2020 May 13;8(2). Epub 2020 May 13.

Institute for Glycomics, Griffith University, Gold Coast 4215, Australia.

Due to the continuing emergence of multidrug resistant strains of there is an urgent need for the development of a gonococcal vaccine. We evaluated the gonococcal heparin binding antigen (NHBA) as a potential vaccine candidate, in terms of its sequence conservation and expression in a range of strains, as well as its immunogenicity and the functional activity of antibodies raised to either the full length NHBA or a C-terminal fragment of NHBA (NHBA-c). The gene encoding NHBA is highly conserved and expressed in all strains investigated. Recombinant NHBA is immunogenic, and mice immunized with either NHBA or NHBA-c adjuvanted with either Freund's or aluminium hydroxide (alum) generated a humoral immune response, with predominantly IgG1 antibodies. Antibodies generated by both NHBA and NHBA-c antigens promoted complement activation and mediated bacterial killing via both serum bactericidal activity and opsonophagocytic activity, with slightly higher titers seen for the NHBA-c antigen. Anti-NHBA was also able to block the functional activity of NHBA by reducing binding to heparin and adherence to cervical and urethral epithelial cells. These data suggest that the gonococcal NHBA is a promising vaccine antigen to include in a vaccine to control .
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http://dx.doi.org/10.3390/vaccines8020219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349534PMC
May 2020

Gonococcal vaccines: Public health value and preferred product characteristics; report of a WHO global stakeholder consultation, January 2019.

Vaccine 2020 06 28;38(28):4362-4373. Epub 2020 Apr 28.

World Health Organization, Geneva, Switzerland.

Renewed interest in developing vaccines against Neisseria gonorrhoeae has been sparked by the increasing threat of gonococcal antimicrobial resistance (AMR) and growing optimism that gonococcal vaccines are biologically feasible. Evidence suggests serogroup B Neisseria meningitidis vaccines might provide some cross-protection against N. gonorrhoeae, and new gonococcal vaccine candidates based on several approaches are currently in preclinical development. To further stimulate investment and accelerate development of gonococcal vaccines, greater understanding is needed regarding the overall value that gonococcal vaccines might have in addressing public health and societal goals in low-, middle-, and high-income country contexts and how future gonococcal vaccines might be accepted and used, if available. In January 2019, the World Health Organization (WHO) convened a multidisciplinary international group of experts to lay the groundwork for understanding the potential health, economic, and societal value of gonococcal vaccines and their likely acceptance and use, and for developing gonococcal vaccine preferred product characteristics (PPCs). WHO PPCs describe preferences for vaccine attributes that would help optimize vaccine value and use in meeting the global public health need. This paper describes the main discussion points and conclusions from the January 2019 meeting of experts. Participants emphasized the need for vaccines to control N. gonorrhoeae infections with the ultimate goals of preventing adverse sexual and reproductive health outcomes (e.g., infertility) and reducing the impact of gonococcal AMR. Meeting participants also discussed important PPC considerations (e.g., vaccine indications, target populations, and potential immunization strategies) and highlighted crucial research and data needs for guiding the value assessment and PPCs for gonococcal vaccines and advancing gonococcal vaccine development.
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http://dx.doi.org/10.1016/j.vaccine.2020.02.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273195PMC
June 2020

Transcriptome RNA Sequencing Data Set of Gene Expression in Moraxella catarrhalis On- and Off-Phase Variants of the Type III DNA Methyltransferase ModM3.

Microbiol Resour Announc 2020 Apr 2;9(14). Epub 2020 Apr 2.

Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia

is a leading bacterial cause of otitis media and exacerbations of chronic obstructive pulmonary disease. Here, we announce a transcriptome RNA sequencing data set detailing global gene expression in two CCRI-195ME variants with expression of the DNA methyltransferase ModM3 phase varied either on or off.
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http://dx.doi.org/10.1128/MRA.01559-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118194PMC
April 2020

Proteome of a Moraxella catarrhalis Strain under Iron-Restricted Conditions.

Microbiol Resour Announc 2020 Mar 19;9(12). Epub 2020 Mar 19.

Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia

is a leading cause of otitis media and exacerbations of chronic obstructive pulmonary disease; however, its response to iron starvation during infection is not completely understood. Here, we announce a sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) data set describing the differential expression of the CCRI-195ME proteome under iron-restricted versus iron-replete conditions.
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http://dx.doi.org/10.1128/MRA.00064-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082453PMC
March 2020

The Moraxella catarrhalis phase-variable DNA methyltransferase ModM3 is an epigenetic regulator that affects bacterial survival in an in vivo model of otitis media.

BMC Microbiol 2019 12 9;19(1):276. Epub 2019 Dec 9.

Institute for Glycomics, Griffith University, Gold Coast, Queensland, 4215, Australia.

Background: Moraxella catarrhalis is a leading cause of otitis media (OM) and chronic obstructive pulmonary disease (COPD). M. catarrhalis contains a Type III DNA adenine methyltransferase (ModM) that is phase-variably expressed (i.e., its expression is subject to random, reversible ON/OFF switching). ModM has six target recognition domain alleles (modM1-6), and we have previously shown that modM2 is the predominant allele, while modM3 is associated with OM. Phase-variable DNA methyltransferases mediate epigenetic regulation and modulate pathogenesis in several bacteria. ModM2 of M. catarrhalis regulates the expression of a phasevarion containing genes important for colonization and infection. Here we describe the phase-variable expression of modM3, the ModM3 methylation site and the suite of genes regulated within the ModM3 phasevarion.

Results: Phase-variable expression of modM3, mediated by variation in length of a 5'-(CAAC)-3' tetranucleotide repeat tract in the open reading frame was demonstrated in M. catarrhalis strain CCRI-195ME with GeneScan fragment length analysis and western immunoblot. We determined that ModM3 is an active N6-adenine methyltransferase that methylates the sequence 5'-ACATC-3'. Methylation was detected at all 4446 5'-ACATC-3' sites in the genome when ModM3 is expressed. RNASeq analysis identified 31 genes that are differentially expressed between modM3 ON and OFF variants, including five genes that are involved in the response to oxidative and nitrosative stress, with potential roles in biofilm formation and survival in anaerobic environments. An in vivo chinchilla (Chinchilla lanigera) model of otitis media demonstrated that transbullar challenge with the modM3 OFF variant resulted in an increased middle ear bacterial load compared to a modM3 ON variant. In addition, co-infection experiments with NTHi and M. catarrhalis modM3 ON or modM3 OFF variants revealed that phase variation of modM3 altered survival of NTHi in the middle ear during early and late stage infection.

Conclusions: Phase variation of ModM3 epigenetically regulates the expression of a phasevarion containing multiple genes that are potentially important in the progression of otitis media.
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http://dx.doi.org/10.1186/s12866-019-1660-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902483PMC
December 2019

Role of the Gonococcal Neisserial Heparin Binding Antigen in Microcolony Formation, and Serum Resistance and Adherence to Epithelial Cells.

J Infect Dis 2020 04;221(10):1612-1622

Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia.

The sexually transmitted infection gonorrhoea is on the rise worldwide and an increased understanding of the mechanisms of colonization and pathogenesis of Neisseria gonorrhoeae is required to aid development of new treatment and prevention strategies. In the current study, we investigate the neisserial heparin-binding antigen (NHBA) of N. gonorrhoeae and confirm its role in binding to several glycans, including heparin, and identify interactions of NHBA with both gonococcal and host cells. Furthermore, we report that a gonococcal nhba mutant displays decreased cell aggregation and microcolony formation, as well as reduced survival in human serum and reduced adherence to human cervical and urethral epithelial cells, relative to the wild-type strain. These data indicate that the gonococcal NHBA contributes to several aspects of the colonization and survival of N. gonorrhoeae and may be a target for new antimicrobial or vaccines.
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http://dx.doi.org/10.1093/infdis/jiz628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184908PMC
April 2020

Non-typeable Haemophilus influenzae isolates from patients with chronic obstructive pulmonary disease contain new phase-variable modA methyltransferase alleles controlling phasevarions.

Sci Rep 2019 11 4;9(1):15963. Epub 2019 Nov 4.

Institute for Glycomics, Griffith University, Gold Coast, Queensland, 4222, Australia.

Phasevarions (phase-variable regulons) are emerging as an important area of bacterial gene regulation. Many bacterial pathogens contain phasevarions, with gene expression controlled by the phase-variable expression of DNA methyltransferases via epigenetic mechanisms. Non-typeable Haemophilus influenzae (NTHi) contains the phase-variable methyltransferase modA, of which multiple allelic variants exist (modA1-21). We have previously demonstrated 5 of 21 these modA alleles are overrepresented in NTHi strains isolated from children with middle ear infections. In this study we investigated the modA allele distribution in NTHi strains isolated from patients with chronic obstructive pulmonary disease, COPD. We demonstrate that the distribution of modA alleles in a large panel of COPD isolates is different to the distribution seen in middle ear infections, suggesting different modA alleles may provide distinct advantages in the differing niches of the middle ear and COPD airways. We also identified two new phase-variable modA alleles - modA15 and modA18 - and demonstrate that these alleles methylate distinct DNA sequences and control unique phasevarions. The modA15 and modA18 alleles have only been observed in COPD isolates, indicating that these two alleles may be markers for isolates likely to cause exacerbations of COPD.
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http://dx.doi.org/10.1038/s41598-019-52429-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828955PMC
November 2019

The meningococcal vaccine antigen GNA2091 is an analogue of YraP and plays key roles in outer membrane stability and virulence.

FASEB J 2019 11 23;33(11):12324-12335. Epub 2019 Aug 23.

GlaxoSmithKline (GSK) Vaccines, Siena, Italy.

GNA2091 is one of the components of the 4-component meningococcal serogroup B vaccine (4CMenB) vaccine and is highly conserved in all meningococcal strains. However, its functional role has not been fully characterized. Here we show that is part of an operon and is cotranscribed with the , and adjacent genes, and a similar but reduced operon arrangement is conserved in many other gram-negative bacteria. Deletion of the gene causes an aggregative phenotype with a mild defect in cell separation; differences in the outer membrane composition and phospholipid profile, in particular in the phosphoethanolamine levels; an increased level of outer membrane vesicles; and deregulation of the zinc-responsive genes such as . Finally, the ∆2091 strain is attenuated with respect to the wild-type strain in competitive index experiments in the infant rat model of meningococcal infection. Altogether these data suggest that GNA2091 plays important roles in outer membrane architecture, biogenesis, homeostasis, and in meningococcal survival , and a model for its role is discussed. These findings highlight the importance of GNA2091 as a vaccine component.-Seib, K. L., Haag, A. F., Oriente, F., Fantappiè, L., Borghi, S., Semchenko, E. A., Schulz, B. L., Ferlicca, F., Taddei, A. R., Giuliani, M. M., Pizza, M., Delany, I. The meningococcal vaccine antigen GNA2091 is an analogue of YraP and plays key roles in outer membrane stability and virulence.
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http://dx.doi.org/10.1096/fj.201900669RDOI Listing
November 2019

Phase-variable bacterial loci: how bacteria gamble to maximise fitness in changing environments.

Biochem Soc Trans 2019 08 24;47(4):1131-1141. Epub 2019 Jul 24.

Institute for Glycomics, Griffith University, Gold Coast, Queensland 4215, Australia

Phase-variation of genes is defined as the rapid and reversible switching of expression - either ON-OFF switching or the expression of multiple allelic variants. Switching of expression can be achieved by a number of different mechanisms. Phase-variable genes typically encode bacterial surface structures, such as adhesins, pili, and lipooligosaccharide, and provide an extra contingency strategy in small-genome pathogens that may lack the plethora of 'sense-and-respond' gene regulation systems found in other organisms. Many bacterial pathogens also encode phase-variable DNA methyltransferases that control the expression of multiple genes in systems called phasevarions (phase-variable regulons). The presence of phase-variable genes allows a population of bacteria to generate a number of phenotypic variants, some of which may be better suited to either colonising certain host niches, surviving a particular environmental condition and/or evading an immune response. The presence of phase-variable genes complicates the determination of an organism's stably expressed antigenic repertoire; many phase-variable genes are highly immunogenic, and so would be ideal vaccine candidates, but unstable expression due to phase-variation may allow vaccine escape. This review will summarise our current understanding of phase-variable genes that switch expression by a variety of mechanisms, and describe their role in disease and pathobiology.
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http://dx.doi.org/10.1042/BST20180633DOI Listing
August 2019

Transcriptome Sequencing Data Sets for Determining Gene Expression Changes Mediated by Phase-Variable DNA Methyltransferases in Nontypeable Haemophilus influenzae Strains Isolated from Patients with Chronic Obstructive Pulmonary Disease.

Microbiol Resour Announc 2019 Jul 18;8(29). Epub 2019 Jul 18.

Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia

Nontypeable (NTHi) is a major bacterial cause of exacerbations in chronic obstructive pulmonary disease (COPD). Here, we report high-depth coverage transcriptome sequencing (RNA-seq) data from two NTHi strains, each encoding a different phase-variable methyltransferase. phase variation results in gene expression differences. These data will serve as an important resource for future studies.
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http://dx.doi.org/10.1128/MRA.00526-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639615PMC
July 2019

Glycointeractome of Neisseria gonorrhoeae: Identification of Host Glycans Targeted by the Gonococcus To Facilitate Adherence to Cervical and Urethral Epithelial Cells.

mBio 2019 07 9;10(4). Epub 2019 Jul 9.

Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia

is a significant threat to global health for which a vaccine and novel treatment options are urgently needed. Glycans expressed by human cells are commonly targeted by pathogens to facilitate interactions with the host, and thus characterization of these interactions can aid identification of bacterial receptors that can be exploited as vaccine and/or drug targets. Using glycan array analysis, we identified 247 specific interactions between and glycans representative of those found on human cells. Interactions included those with mannosylated, fucosylated, and sialylated glycans, glycosaminoglycans (GAGs), and glycans terminating with galactose (Gal), -acetylgalactosamine (GalNAc), and -acetylglucosamine (GlcNAc). By investigating the kinetics of interactions with selected glycans, we demonstrate that whole-cell has a high affinity for mannosylated glycans (dissociation constant [ ], 0.14 to 0.59 μM), which are expressed on the surface of cervical and urethral epithelial cells. Using chromatography coupled with mass spectrometric (MS) analysis, we identified potential mannose-binding proteins in Pretreatment of cells with mannose-specific lectin (concanavalin A) or free mannose competitor (α-methyl-d-mannopyranoside) substantially reduced gonococcal adherence to epithelial cells. This suggests that targets mannosyl glycans to facilitate adherence to host cells and that mannosides or similar compounds have the potential to be used as a novel treatment option for Multidrug-resistant strains of are emerging worldwide, and novel treatment and prevention strategies are needed. Glycans are ubiquitously expressed by all human cells and can be specifically targeted by pathogens to facilitate association with host cells. Here we identify and characterize the host-glycan binding profile (glycointeractome), which revealed numerous interactions, including high-affinity binding to mannosyl glycans. We identify gonococcal potential mannose-binding proteins and show that uses mannosyl glycans expressed on the surface of cervical and urethral epithelia to facilitate adherence. Furthermore, a mannose-binding lectin or a mannoside compound was able to reduce this adherence. By characterizing the glycointeractome of we were able to elucidate a novel mechanism used by this important pathogen to interact with human cells, and this interaction could be exploited to develop novel therapeutics to treat antibiotic-resistant gonorrhea.
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http://dx.doi.org/10.1128/mBio.01339-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747729PMC
July 2019

Antimicrobial susceptibility and impact of macrolide antibiotics on Moraxella catarrhalis in the upper and lower airways of children with chronic endobronchial suppuration.

J Med Microbiol 2019 Aug 5;68(8):1140-1147. Epub 2019 Jul 5.

Child Health Division, Menzies School of Health Research, Darwin, Northern Territory 0811, Australia.

Introduction: Moraxella catarrhalis is an important but insufficiently studied respiratory pathogen.

Aim: To determine antibiotic susceptibility and impact of recent antibiotics on M. catarrhalis from children with chronic endobronchial suppuration.

Methodology: We cultured nasopharyngeal (NP) swabs and bronchoalveolar lavage (BAL) fluids collected from children who were prospectively enrolled in studies of chronic cough and had flexible bronchoscopy performed. Recent β-lactam or macrolide antibiotic use was recorded. M. catarrhalis isolates stored at -80 °C were re-cultured and susceptibility determined to a range of antibiotics including the macrolide antibiotic erythromycin.

Results: Data from concurrently collected NP and BAL specimens were available from 547 children (median age 2.4 years) enrolled from 2007 to 2016. M. catarrhalis NP carriage was detected in 149 (27  %) children and lower airway infection (≥10 c.f.u. ml BAL) in 67 (12  %) children. In total, 91  % of 222 M. catarrhalis isolates were β-lactamase producers, and non-susceptibility was high to benzylpenicillin (98 %), cefaclor (39 %) and cotrimoxazole (38 %). Overall, >97  % isolates were susceptible to cefuroxime, chloramphenicol, erythromycin and tetracycline; three isolates were erythromycin-resistant (MIC >0.5 mg l). Recent macrolide antibiotics (n=152 children, 28 %) were associated with significantly reduced M. catarrhalis carriage and lower airway infection episodes compared to children who did not receive macrolides; odds ratios 0.19 (95  % CI 0.10-0.35) and 0.15 (0.04-0.41), respectively.

Conclusion: Despite the frequent use of macrolides, few macrolide-resistant isolates were detected. This suggests a fitness cost associated with macrolide resistance in M. catarrhalis. Macrolide antibiotics remain an effective choice for treating M. catarrhalis lower airway infection in children with chronic endobronchial suppuration.
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http://dx.doi.org/10.1099/jmm.0.001033DOI Listing
August 2019

Phasevarions of bacterial pathogens - phase-variable epigenetic regulators evolving from restriction-modification systems.

Microbiology (Reading) 2019 09 17;165(9):917-928. Epub 2019 Apr 17.

Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia.

Phase-variable DNA methyltransferases control the expression of multiple genes via epigenetic mechanisms in a wide variety of bacterial species. These systems are called phasevarions, for phase-variable regulons. Phasevarions regulate genes involved in pathogenesis, host adaptation and antibiotic resistance. Many human-adapted bacterial pathogens contain phasevarions. These include leading causes of morbidity and mortality worldwide, such as non-typeable , and spp. Phase-variable methyltransferases and phasevarions have also been discovered in environmental organisms and veterinary pathogens. The existence of many different examples suggests that phasevarions have evolved multiple times as a contingency strategy in the bacterial domain, controlling phenotypes that are important in adapting to environmental change. Many of the organisms that contain phasevarions have existing or emerging drug resistance. Vaccines may therefore represent the best and most cost-effective tool to prevent disease caused by these organisms. However, many phasevarions also control the expression of current and putative vaccine candidates; variable expression of antigens could lead to immune evasion, meaning that vaccines designed using these targets become ineffective. It is therefore essential to characterize phasevarions in order to determine an organism's stably expressed antigenic repertoire, and rationally design broadly effective vaccines.
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http://dx.doi.org/10.1099/mic.0.000805DOI Listing
September 2019

Lectin activity of Pseudomonas aeruginosa vaccine candidates PSE17-1, PSE41-5 and PSE54.

Biochem Biophys Res Commun 2019 05 3;513(1):287-290. Epub 2019 Apr 3.

Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia. Electronic address:

Pseudomonas aeruginosa is an opportunistic pathogen that causes nosocomial infections most commonly in immunocompromised, cystic fibrosis (CF) and burns patients. The pilin and Pseudomonas lectins 1 (PA-IL) and 2 (PA-IIL) are known glycan-binding proteins of P. aeruginosa that are involved in adherence to host cells, particularly CF host airways. Recently, new P. aeruginosa surface proteins were identified by reverse vaccinology and tested in vivo as potential vaccine antigens. Three of these, namely PSE17-1, PSE41-5 and PSE54, were screened for glycan binding using glycan arrays displaying glycan structures representative of those found on human cells. Surface plasmon resonance was used to confirm the lectin activity of these proteins, and determined affinities with several host glycans to be in the nanomolar range. PSE17-1 binds hyaluronic acid and sialyl Lewis A and X. PSE41-5 binds terminal β-linked galactose structures, Lewis and ABO blood group antigens. PSE54 binds to ABO blood group antigens and some terminal β-linked galactose. All three proteins are novel lectins of P. aeruginosa with potential roles in infection of host cells.
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http://dx.doi.org/10.1016/j.bbrc.2019.03.092DOI Listing
May 2019

Investigation of Whole Cell Meningococcal Glycan Interactions Using High Throughput Glycobiology Techniques: Glycan Array and Surface Plasmon Resonance.

Methods Mol Biol 2019 ;1969:113-121

Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.

A growing body of evidence suggests that glycans are important for meningococcal host-pathogen interactions and virulence. The development of glycobiology techniques such as glycan array analysis and surface plasmon resonance (SPR) has increased awareness of the importance of glycans in biological processes and has increased the interest of their study. While these techniques are more routinely used with purified proteins, there is growing interest in their applicability to cell-based studies, to better emulate host-pathogen interactions in vivo. Here we describe the use of glycan array analysis and SPR for the investigation of glycan binding by Neisseria meningitidis cells. Used together, these methods can help identify and characterize N. meningitidis glycointeractions.
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http://dx.doi.org/10.1007/978-1-4939-9202-7_8DOI Listing
September 2019

Screening DNA Repeat Tracts of Phase Variable Genes by Fragment Analysis.

Methods Mol Biol 2019 ;1969:93-104

Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.

Fragment analysis (or fragment length analysis) is a PCR-based method which allows quantification of the size and proportion of a DNA repeat tract length of a phase-variable region. Primers are labeled with a fluorescent dye, the resulting amplicons are processed by capillary electrophoresis, and results are analyzed for amplicon size and proportion by associated software (such as Peakscanner). Here we describe the process of designing primers and controls to screen for the number of repeats in a polymeric tract of a phase-variable gene in Neisseria meningitidis (the DNA methyltransferase ModA is used as an example, but this method can be applied to other phase-variable genes).
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http://dx.doi.org/10.1007/978-1-4939-9202-7_6DOI Listing
September 2019

Analysis of Invasive Nontypeable Isolates Reveals Selection for the Expression State of Particular Phase-Variable Lipooligosaccharide Biosynthetic Genes.

Infect Immun 2019 03 23;87(5). Epub 2019 Apr 23.

Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia

Nontypeable (NTHi) is a major human pathogen, responsible for several acute and chronic infections of the respiratory tract. The incidence of invasive infections caused by NTHi is increasing worldwide. NTHi is able to colonize the nasopharynx asymptomatically, and the exact change(s) responsible for transition from benign carriage to overt disease is not understood. We have previously reported that phase variation (the rapid and reversible ON-OFF switching of gene expression) of particular lipooligosaccharide (LOS) glycosyltransferases occurs during transition from colonizing the nasopharynx to invading the middle ear. Variation in the structure of the LOS is dependent on the ON/OFF expression status of each of the glycosyltransferases responsible for LOS biosynthesis. In this study, we surveyed a collection of invasive NTHi isolates for ON/OFF expression status of seven phase-variable LOS glycosyltransferases. We report that the expression state of the LOS biosynthetic genes ON and OFF shows a correlation with invasive NTHi isolates. We hypothesize that these gene expression changes contribute to the invasive potential of NTHi. OafA expression, which is responsible for the addition of an -acetyl group onto the LOS, has been shown to impart a phenotype of increased serum resistance and may serve as a marker for invasive NTHi.
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http://dx.doi.org/10.1128/IAI.00093-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479036PMC
March 2019

Moraxella catarrhalis NucM is an entry nuclease involved in extracellular DNA and RNA degradation, cell competence and biofilm scaffolding.

Sci Rep 2019 02 22;9(1):2579. Epub 2019 Feb 22.

Institute for Glycomics, Griffith University, Gold Coast, Queensland, 4215, Australia.

Moraxella catarrhalis is a host-adapted bacterial pathogen that causes otitis media and exacerbations of chronic obstructive pulmonary disease. This study characterises the conserved M. catarrhalis extracellular nuclease, a member of the ββα metal finger family of nucleases, that we have named NucM. NucM shares conserved sequence motifs from the ββα nuclease family, including the DRGH catalytic core and Mg co-ordination site, but otherwise shares little primary sequence identity with other family members, such as the Serratia Nuc and pneumococcal EndA nucleases. NucM is secreted from the cell and digests linear and circular nucleic acid. However, it appears that a proportion of NucM is also associated with the cell membrane and acts as an entry nuclease, facilitating transformation of M. catarrhalis cells. This is the first example of a ββα nuclease in a Gram negative bacteria that acts as an entry nuclease. In addition to its role in competence, NucM affects cell aggregation and biofilm formation by M. catarrhalis, with ΔnucM mutants having increased biofilm biomass. NucM is likely to increase the ability of cells to survive and persist in vivo, increasing the virulence of M. catarrhalis and potentially affecting the behaviour of other pathogens that co-colonise the otorhinolaryngological niche.
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http://dx.doi.org/10.1038/s41598-019-39374-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384898PMC
February 2019

The Methionine Sulfoxide Reductase (MsrA/B) Is a Surface Exposed, Immunogenic, Vaccine Candidate.

Front Immunol 2019 6;10:137. Epub 2019 Feb 6.

Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.

Control of the sexually transmitted infection gonorrhea is a major public health challenge, due to the recent emergence of multidrug resistant strains of , and there is an urgent need for novel therapies or a vaccine to prevent gonococcal disease. In this study, we evaluated the methionine sulfoxide reductase (MsrA/B) of as a potential vaccine candidate, in terms of its expression, sequence conservation, localization, immunogenicity, and the functional activity of antibodies raised to it. Gonococcal MsrA/B has previously been shown to reduce methionine sulfoxide [Met(O)] to methionine (Met) in oxidized proteins and protect against oxidative stress. Here we have shown that the gene encoding MsrA/B is present, highly conserved, and expressed in all strains investigated, and we determined that MsrA/B is surface is exposed on . Recombinant MsrA/B is immunogenic, and mice immunized with MsrA/B and either aluminum hydroxide gel adjuvant or Freund's adjuvant generated a humoral immune response, with predominantly IgG1 antibodies. Higher titers of IgG2a, IgG2b, and IgG3 were detected in mice immunized with MsrA/B-Freund's adjuvant compared to MsrA/B-aluminum hydroxide adjuvant, while IgM titers were similar for both adjuvants. Antibodies generated by MsrA/B-Freund's in mice mediated bacterial killing via both serum bactericidal activity and opsonophagocytic activity. Anti-MsrA/B was also able to functionally block the activity of MsrA/B by inhibiting binding to its substrate, Met(O). We propose that recombinant MsrA/B is a promising vaccine antigen for .
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http://dx.doi.org/10.3389/fimmu.2019.00137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372556PMC
January 2020

Modelling the in-host dynamics of Neisseria gonorrhoeae infection.

Pathog Dis 2019 02;77(1)

Faculty of Medicine, School of Public Health and Community Medicine, UNSW Sydney, Samuels Avenue, Kensington, NSW 2052, Australia.

The bacterial species Neisseria gonorrhoeae (NG) has evolved to replicate effectively and exclusively in human epithelia, with its survival dependent on complex interactions between bacteria, host cells and antimicrobial agents. A better understanding of these interactions is needed to inform development of new approaches to gonorrhoea treatment and prevention but empirical studies have proven difficult, suggesting a role for mathematical modelling. Here, we describe an in-host model of progression of untreated male symptomatic urethral infection, including NG growth and interactions with epithelial cells and neutrophils, informed by in vivo and in vitro studies. The model reproduces key observations on bacterial load and clearance and we use multivariate sensitivity analysis to refine plausible ranges for model parameters. Model variants are also shown to describe mouse infection dynamics with altered parameter ranges that correspond to observed differences between human and mouse infection. Our results highlight the importance of NG internalisation, particularly within neutrophils, in sustaining infection in the human model, with ∼80% of the total NG population internalised from day 25 on. This new mechanistic model of in-host NG infection dynamics should also provide a platform for future studies relating to antimicrobial treatment and resistance and infection at other anatomical sites.
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http://dx.doi.org/10.1093/femspd/ftz008DOI Listing
February 2019

Nasal swab bacteriology by PCR during the first 24-months of life: A prospective birth cohort study.

Pediatr Pulmonol 2019 03 4;54(3):289-296. Epub 2019 Jan 4.

Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia.

Background: Most respiratory bacterial carriage studies in children are based on cross-sectional samples or longitudinal studies with infrequent sampling points. The prospective Observational Research in Childhood Infectious Diseases birth cohort study intensively evaluated the community-based epidemiology of respiratory viruses and bacteria during the first 2-years of life. Here we report the bacteriologic findings.

Methods: Pregnant women in Brisbane, Australia were recruited between September 2010 and October 2012, and their healthy newborn children were followed for the first 2-years of life. Parents kept a daily symptom diary for the study child, collected a weekly anterior nose swab and completed an illness burden diary when their child met pre-defined illness criteria. Specimens were tested for respiratory bacteria by real-time polymerase chain reaction (PCR) assays and those containing human genomic DNA, deemed as high-quality, were analyzed.

Results: Altogether 8100 high-quality nasal swab specimens from 158 enrolled children were analyzed. Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae were detected in 42.4%, 38.9%, and 14.8% of these samples, respectively. Concomitant detection of bacteria was common. In contrast, Bordetella pertussis, B. parapertussis, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Simkania negevensis were rarely identified. The prevalence of the three major bacteria was higher with increasing age and in the winter and spring months. Siblings and childcare attendance were the other risk factors identified.

Conclusions: We confirmed the feasibility of frequent nasal swabbing by parents for studying bacterial colonization. PCR detected the major respiratory tract bacteria with expected high frequencies, but atypical bacteria were found rarely in this cohort.
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http://dx.doi.org/10.1002/ppul.24231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167656PMC
March 2019

The Serogroup B Meningococcal Vaccine Bexsero Elicits Antibodies to Neisseria gonorrhoeae.

Clin Infect Dis 2019 09;69(7):1101-1111

Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia.

Background: Neisseria gonorrhoeae and Neisseria meningitidis are closely-related bacteria that cause a significant global burden of disease. Control of gonorrhoea is becoming increasingly difficult, due to widespread antibiotic resistance. While vaccines are routinely used for N. meningitidis, no vaccine is available for N. gonorrhoeae. Recently, the outer membrane vesicle (OMV) meningococcal B vaccine, MeNZB, was reported to be associated with reduced rates of gonorrhoea following a mass vaccination campaign in New Zealand. To probe the basis for this protection, we assessed the cross-reactivity to N. gonorrhoeae of serum raised to the meningococcal vaccine Bexsero, which contains the MeNZB OMV component plus 3 recombinant antigens (Neisseria adhesin A, factor H binding protein [fHbp]-GNA2091, and Neisserial heparin binding antigen [NHBA]-GNA1030).

Methods: A bioinformatic analysis was performed to assess the similarity of MeNZB OMV and Bexsero antigens to gonococcal proteins. Rabbits were immunized with the OMV component or the 3 recombinant antigens of Bexsero, and Western blots and enzyme-linked immunosorbent assays were used to assess the generation of antibodies recognizing N. gonorrhoeae. Serum from humans immunized with Bexsero was investigated to assess the nature of the anti-gonococcal response.

Results: There is a high level of sequence identity between MeNZB OMV and Bexsero OMV antigens, and between the antigens and gonococcal proteins. NHBA is the only Bexsero recombinant antigen that is conserved and surfaced exposed in N. gonorrhoeae. Bexsero induces antibodies in humans that recognize gonococcal proteins.

Conclusions: The anti-gonococcal antibodies induced by MeNZB-like OMV proteins could explain the previously-seen decrease in gonorrhoea following MeNZB vaccination. The high level of human anti-gonococcal NHBA antibodies generated by Bexsero vaccination may provide additional cross-protection against gonorrhoea.
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http://dx.doi.org/10.1093/cid/ciy1061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743822PMC
September 2019

Closed Complete Genome Sequences of Two Nontypeable Haemophilus influenzae Strains Containing Novel Alleles from the Sputum of Patients with Chronic Obstructive Pulmonary Disease.

Microbiol Resour Announc 2018 Jul 19;7(2). Epub 2018 Jul 19.

Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia.

Nontypeable Haemophilus influenzae (NTHi) is an important bacterial pathogen that causes otitis media and exacerbations of chronic obstructive pulmonary disease (COPD). Here, we report the complete genome sequences of NTHi strains 10P129H1 and 84P36H1, isolated from COPD patients, which contain the phase-variable epigenetic regulators ModA15 and ModA18, respectively.
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http://dx.doi.org/10.1128/MRA.00821-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211359PMC
July 2018

Lectin Activity of the TcdA and TcdB Toxins of Clostridium difficile.

Infect Immun 2019 03 21;87(3). Epub 2019 Feb 21.

Institute for Glycomics, Griffith University, Gold Coast, Australia

is a major cause of hospital-acquired antibiotic-associated diarrhea. produces two cytotoxins, TcdA and TcdB; both toxins are multidomain proteins that lead to cytotoxicity through the modification and inactivation of small GTPases of the Rho/Rac family. Previous studies have indicated that host glycans are targets for TcdA and TcdB, with interactions thought to be with both α- and β-linked galactose. In the current study, screening of glycan arrays with different domains of TcdA and TcdB revealed that the binding regions of both toxins interact with a wider range of host glycoconjugates than just terminal α- and β-linked galactose, including blood groups, Lewis antigens, -acetylglucosamine, mannose, and glycosaminoglycans. The interactions of TcdA and TcdB with ABO blood group and Lewis antigens were assessed by surface plasmon resonance (SPR). The blood group A antigen was the highest-affinity ligand for both toxins. Free glycans alone or in combination were unable to abolish Vero cell cytotoxicity by TcdB. SPR competition assays indicate that there is more than one glycan binding site on TcdB. Host glycoconjugates are common targets of bacterial toxins, but typically this binding is to a specific structure or related structures. The binding of TcdA and TcdB is to a wide range of host glycans providing a wide range of target cells and tissues .
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http://dx.doi.org/10.1128/IAI.00676-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386544PMC
March 2019

Moraxella catarrhalis Restriction-Modification Systems Are Associated with Phylogenetic Lineage and Disease.

Genome Biol Evol 2018 11 1;10(11):2932-2946. Epub 2018 Nov 1.

Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia.

Moraxella catarrhalis is a human-adapted pathogen, and a major cause of otitis media (OM) and exacerbations of chronic obstructive pulmonary disease. The species is comprised of two main phylogenetic lineages, RB1 and RB2/3. Restriction-modification (R-M) systems are among the few lineage-associated genes identified in other bacterial genera and have multiple functions including defense against foreign invading DNA, maintenance of speciation, and epigenetic regulation of gene expression. Here, we define the repertoire of R-M systems in 51 publicly available M. catarrhalis genomes and report their distribution among M. catarrhalis phylogenetic lineages. An association with phylogenetic lineage (RB1 or RB2/3) was observed for six R-M systems, which may contribute to the evolution of the lineages by restricting DNA transformation. In addition, we observed a relationship between a mutually exclusive Type I R-M system and a Type III R-M system at a single locus conserved throughout a geographically and clinically diverse set of M. catarrhalis isolates. The Type III R-M system at this locus contains the phase-variable Type III DNA methyltransferase, modM, which controls a phasevarion (phase-variable regulon). We observed an association between modM presence and OM-associated middle ear isolates, indicating a potential role for ModM-mediated epigenetic regulation in OM pathobiology.
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http://dx.doi.org/10.1093/gbe/evy226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241649PMC
November 2018

Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides.

FASEB J 2019 02 27;33(2):2095-2104. Epub 2018 Sep 27.

Institute for Glycomics, Griffith University, Queensland, Australia.

Bacterial infection is one of the leading causes of death in young, elderly, and immune-compromised patients. The rapid spread of multi-drug-resistant (MDR) bacteria is a global health emergency and there is a lack of new drugs to control MDR pathogens. We describe a heretofore-unexplored discovery pathway for novel antibiotics that is based on self-targeting, structure-disrupting peptides. We show that a helical peptide, KFF- EcH3, derived from the Escherichia coli methionine aminopeptidase can disrupt secondary and tertiary structure of this essential enzyme, thereby killing the bacterium (including MDR strains). Significantly, no detectable resistance developed against this peptide. Based on a computational analysis, our study predicted that peptide KFF- EcH3 has the strongest interaction with the structural core of the methionine aminopeptidase. We further used our approach to identify peptide KFF- NgH1 to target the same enzyme from Neisseria gonorrhoeae. This peptide inhibited bacterial growth and was able to treat a gonococcal infection in a human cervical epithelial cell model. These findings present an exciting new paradigm in antibiotic discovery using self-derived peptides that can be developed to target the structures of any essential bacterial proteins.-Zhan, J., Jia, H., Semchenko, E. A., Bian, Y., Zhou, A. M., Li, Z., Yang, Y., Wang, J., Sarkar, S., Totsika, M., Blanchard, H., Jen, F. E.-C., Ye, Q., Haselhorst, T., Jennings, M. P., Seib, K. L., Zhou, Y. Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides.
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http://dx.doi.org/10.1096/fj.201700613RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338635PMC
February 2019