ATP-Binding Cassette Transporters Are Targets for the Development of Antibacterial Vaccines and Therapies

Garmory, Helen S; Titball, Richard W.

doi:10.1128/iai.72.12.6757-6763.2004

Cited by 265 publications

(229 citation statements)

References 83 publications

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“…Interpretation of the contribution of MtsR in virulence is complicated by the redundancy of GAS iron acquisition systems and metal homeostasis regulators. Current understanding posits that this redundancy permits pathogenic bacteria to use different sources of iron in different host niches (25). It has been suggested that because of the different sources of iron (ferrichrome, free Fe ions, or heme) used by the GAS transporters, they may differ in importance to pathogenesis depending on the iron source available at the site of infection (26).…”

Section: Invasive and Carrier Relationships And Polymorphism Associatmentioning

confidence: 99%

Molecular genetic anatomy of inter- and intraserotype variation in the human bacterial pathogen group A Streptococcus

Beres

Richter

Nagiec

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

202

177

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In recent years we have studied the relationship between strain genotypes and patient phenotypes in group A Streptococcus (GAS), a model human bacterial pathogen that causes extensive morbidity and mortality worldwide. We have concentrated our efforts on serotype M3 organisms because these strains are common causes of pharyngeal and invasive infections, produce unusually severe invasive infections, and can exhibit epidemic behavior. Our studies have been hindered by the lack of genome-scale phylogenies of multiple GAS strains and whole-genome sequences of multiple serotype M3 strains recovered from individuals with defined clinical phenotypes. To remove some of these impediments, we sequenced to closure the genome of four additional GAS strains and conducted comparative genomic resequencing of 12 contemporary serotype M3 strains representing distinct genotypes and phenotypes. Serotype M3 strains are a single phylogenetic lineage. Strains from asymptomatic throat carriers were significantly less virulent for mice than sterile-site isolates and evolved to a less virulent phenotype by multiple genetic pathways. Strain persistence or extinction between epidemics was strongly associated with presence or absence, respectively, of the prophage encoding streptococcal pyrogenic exotoxin A. A serotype M3 clone significantly underrepresented among necrotizing fasciitis cases has a unique frameshift mutation that truncates MtsR, a transcriptional regulator controlling expression of genes encoding ironacquisition proteins. Expression microarray analysis of this clone confirmed significant alteration in expression of genes encoding iron metabolism proteins. Our analysis provided unprecedented detail about the molecular anatomy of bacterial strain genotypepatient phenotype relationships.carrier ͉ epidemic ͉ genomic resequencing ͉ SNP ͉ phylogeny M icrobial epidemics have repeatedly altered the course of history by decimating human populations, killing domesticated animals, and blighting crops. Despite the impact of these destructive events, we know relatively little about the evolutionary genetic events contributing to bacterial strain emergence and diversification within and between epidemic waves. Also poorly understood is the molecular basis of intraspecies variation in disease phenotype. The recent confluence of genome sequencing and development of high-throughput techniques to interrogate genetic polymorphisms in large samples of strains now permits these topics to be studied at the individual nucleotide level.Group A Streptococcus (GAS) infects humans worldwide and causes an array of diseases ranging from superficial infections such as pharyngitis to fulminant invasive infections characterized by high morbidity and mortality (1, 2). In recent years, we have used serotype M3 GAS strains as model pathogens for studying the molecular processes contributing to clone emergence, epidemic waves, and genotype-phenotype relationships (M protein is a highly polymorphic cell-surface molecule that is antiphagocytic and forms the bas...

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Section: Invasive and Carrier Relationships And Polymorphism Associatmentioning

confidence: 99%

Molecular genetic anatomy of inter- and intraserotype variation in the human bacterial pathogen group A Streptococcus

Beres

Richter

Nagiec

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

202

177

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“…Membrane transporters have been described as virulence-related proteins, as they may be associated with multidrug resistance, metal ions uptake, and cell attachment [34], which are important for bacterial survival, and host colonization. M. hyopneumoniae and M. flocculare genomes have ~ 80 membrane transporters coding genes each, including genes coding for ABC transporters, permeases and PTS systems.…”

Section: Discussionmentioning

confidence: 99%

Comparative proteomics of twoMycoplasma hyopneumoniaestrains andMycoplasma flocculareidentified potential porcine enzootic pneumonia determinants

et al. 2018

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Mycoplasma hyopneumoniae and Mycoplasma flocculare are genetically similar bacteria, which coinhabit the porcine respiratory tract. These mycoplasmas share most of the known virulence factors, but, while M. hyopneumoniae causes porcine enzootic pneumonia (PEP), M. flocculare is a commensal species. To identify potential PEP determinants and provide novel insights on mycoplasma-host interactions, the whole cell proteomes of two M. hyopneumoniae strains, one pathogenic (7448) and other non-pathogenic (J), and M. flocculare were compared. A cell fractioning approach combined with mass spectrometry (LC-MS/MS) proteomics was used to analyze cytoplasmic and surface-enriched protein fractions. Average detection of ~ 50% of the predicted proteomes of M. hyopneumoniae 7448 and J, and M. flocculare was achieved. Many of the identified proteins were differentially represented in M. hyopneumoniae 7448 in comparison to M. hyopneumoniae J and M. flocculare, including potential PEP determinants, such as adhesins, proteases, and redox-balancing proteins, among others. The LC-MS/MS data also provided experimental validation for several genes previously regarded as hypothetical for all analyzed mycoplasmas, including some coding for proteins bearing virulence-related functional domains. The comprehensive proteome profiling of two M. hyopneumoniae strains and M. flocculare provided tens of novel candidates to PEP determinants or virulence factors, beyond those classically described.

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“…secD (protein translocase subunit SecD) a part of the Sec protein translocase complex, tatC (Sec-independent protein translocase protein TatC) an important part of the twin-arginine translocation (Tat) system and Cj1094c (Putative preprotein translocase protein) transports large proteins across membranes. The twin-arginine translocation (TAT) pathway is important to bacterial growth and virulence (Ding and Christie, 2003; Lavander et al, (Garmory and Titball, 2004;Harris et al, 2011). Peptidoglycan is an important component of bacterial cell wall, responsible for maintaining a definite cell shape and primarily conferring mechanical resistance to higher osmotic pressure (Vollmer et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Novel Drug Targets for Food-Borne PathogenCampylobacter jejuni: An Integrated Subtractive Genomics and Comparative Metabolic Pathway Study

Mehla

Ramana

2015

OMICS: A Journal of Integrative Biology

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Campylobacters are a major global health burden and a cause of food-borne diarrheal illness and economic loss worldwide. In developing countries, Campylobacter infections are frequent in children under age two and may be associated with mortality. In developed countries, they are a common cause of bacterial diarrhea in early adulthood. In the United States, antibiotic resistance against Campylobacter is notably increased from 13% in 1997 to nearly 25% in 2011. Novel drug targets are urgently needed but remain a daunting task to accomplish. We suggest that omics-guided drug discovery is timely and worth considering in this context. The present study employed an integrated subtractive genomics and comparative metabolic pathway analysis approach. We identified 16 unique pathways from Campylobacter when compared against H. sapiens with 326 non-redundant proteins; 115 of these were found to be essential in the Database of Essential Genes. Sixty-six proteins among these were non-homologous to the human proteome. Six membrane proteins, of which four are transporters, have been proposed as potential vaccine candidates. Screening of 66 essential non-homologous proteins against DrugBank resulted in identification of 34 proteins with drug-ability potential, many of which play critical roles in bacterial growth and survival. Out of these, eight proteins had approved drug targets available in DrugBank, the majority serving crucial roles in cell wall synthesis and energy metabolism and therefore having the potential to be utilized as drug targets. We conclude by underscoring that screening against these proteins with inhibitors may aid in future discovery of novel therapeutics against campylobacteriosis in ways that will be pathogen specific, and thus have minimal toxic effect on host. Omics-guided drug discovery and bioinformatics analyses offer the broad potential for veritable advances in global health relevant novel therapeutics.

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ATP-Binding Cassette Transporters Are Targets for the Development of Antibacterial Vaccines and Therapies

Cited by 265 publications

References 83 publications

Molecular genetic anatomy of inter- and intraserotype variation in the human bacterial pathogen group A Streptococcus

Molecular genetic anatomy of inter- and intraserotype variation in the human bacterial pathogen group A Streptococcus

Comparative proteomics of twoMycoplasma hyopneumoniaestrains andMycoplasma flocculareidentified potential porcine enzootic pneumonia determinants

Novel Drug Targets for Food-Borne PathogenCampylobacter jejuni: An Integrated Subtractive Genomics and Comparative Metabolic Pathway Study

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