scholarly journals In Vivo Targeting of Clostridioides difficile Using Phage-Delivered CRISPR-Cas3 Antimicrobials

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Kurt Selle ◽  
Joshua R. Fletcher ◽  
Hannah Tuson ◽  
Daniel S. Schmitt ◽  
Lana McMillan ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Broad Spectrum ◽  
Bacterial Species ◽  
Bacterial Genome ◽  
The United States ◽  
Type I ◽  
Content Type ◽  
Clostridioides Difficile

ABSTRACT Clostridioides difficile is an important nosocomial pathogen that causes approximately 500,000 cases of C. difficile infection (CDI) and 29,000 deaths annually in the United States. Antibiotic use is a major risk factor for CDI because broad-spectrum antimicrobials disrupt the indigenous gut microbiota, decreasing colonization resistance against C. difficile. Vancomycin is the standard of care for the treatment of CDI, likely contributing to the high recurrence rates due to the continued disruption of the gut microbiota. Thus, there is an urgent need for the development of novel therapeutics that can prevent and treat CDI and precisely target the pathogen without disrupting the gut microbiota. Here, we show that the endogenous type I-B CRISPR-Cas system in C. difficile can be repurposed as an antimicrobial agent by the expression of a self-targeting CRISPR that redirects endogenous CRISPR-Cas3 activity against the bacterial chromosome. We demonstrate that a recombinant bacteriophage expressing bacterial genome-targeting CRISPR RNAs is significantly more effective than its wild-type parent bacteriophage at killing C. difficile both in vitro and in a mouse model of CDI. We also report that conversion of the phage from temperate to obligately lytic is feasible and contributes to the therapeutic suitability of intrinsic C. difficile phages, despite the specific challenges encountered in the disease phenotypes of phage-treated animals. Our findings suggest that phage-delivered programmable CRISPR therapeutics have the potential to leverage the specificity and apparent safety of phage therapies and improve their potency and reliability for eradicating specific bacterial species within complex communities, offering a novel mechanism to treat pathogenic and/or multidrug-resistant organisms. IMPORTANCE Clostridioides difficile is a bacterial pathogen responsible for significant morbidity and mortality across the globe. Current therapies based on broad-spectrum antibiotics have some clinical success, but approximately 30% of patients have relapses, presumably due to the continued perturbation to the gut microbiota. Here, we show that phages can be engineered with type I CRISPR-Cas systems and modified to reduce lysogeny and to enable the specific and efficient targeting and killing of C. difficile in vitro and in vivo. Additional genetic engineering to disrupt phage modulation of toxin expression by lysogeny or other mechanisms would be required to advance a CRISPR-enhanced phage antimicrobial for C. difficile toward clinical application. These findings provide evidence into how phage can be combined with CRISPR-based targeting to develop novel therapies and modulate microbiomes associated with health and disease.

scholarly journals Metabolic Basis for Mutualism between Gut Bacteria and Its Impact on theDrosophila melanogasterHost

2018 ◽  
Vol 85 (2) ◽  
Author(s):  
Andrew J. Sommer ◽  
Peter D. Newell
Keyword(s):  
Gut Microbiota ◽  
Bacterial Species ◽  
Waste Products ◽  
Fermentation Products ◽  
Content Type ◽  
Starting Point ◽  
Host Physiology ◽  
The Impact

ABSTRACTInteractions between species shape the formation and function of microbial communities. In the gut microbiota of animals, cross-feeding of metabolites between microbes can enhance colonization and influence host physiology. We examined a mutually beneficial interaction between two bacteria isolated from the gut microbiota ofDrosophila, i.e.,Acetobacter fabarumandLactobacillus brevis. After developing anin vitrococulture assay, we utilized a genetic screen to identifyA. fabarumgenes required for enhanced growth withL. brevis. The screen, and subsequent genetic analyses, showed that the gene encoding pyruvate phosphate dikinase (ppdK) is required forA. fabarumto benefit fully from coculture. By testing strains with mutations in a range of metabolic genes, we provide evidence thatA. fabarumcan utilize multiple fermentation products ofL. brevis. Mutualism between the bacteriain vivoaffects gnotobioticDrosophila melanogaster; flies associated withA. fabarumandL. brevisshowed >1,000-fold increases in bacterial cell density and significantly lower triglyceride storage than monocolonized flies. Mutation ofppdKdecreasedA. fabarumdensity in flies cocolonized withL. brevis, consistent with the model in whichAcetobacteremploys gluconeogenesis to assimilateLactobacillusfermentation products as a source of carbonin vivo. We propose that cross-feeding between these groups is a common feature of microbiota inDrosophila.IMPORTANCEThe digestive tracts of animals are home to a community of microorganisms, the gut microbiota, which affects the growth, development, and health of the host. Interactions among microbes in this inner ecosystem can influence which species colonize the gut and can lead to changes in host physiology. We investigated a mutually beneficial interaction between two bacterial species from the gut microbiota of fruit flies. By coculturing the bacteriain vitro, we were able to identify a metabolic gene required for the bacteria to grow better together than they do separately. Our data suggest that one species consumes the waste products of the other, leading to greater productivity of the microbial community and modifying the nutrients available to the host. This study provides a starting point for investigating how these and other bacteria mutually benefit by sharing metabolites and for determining the impact of mutualism on host health.

scholarly journals Dissecting Individual Interactions between Pathogenic and Commensal Bacteria within a Multispecies Gut Microbial Community

mSphere ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Jack Hassall ◽  
Jeffrey K. J. Cheng ◽  
Meera Unnikrishnan
Keyword(s):  
Gut Microbiota ◽  
Bacterial Species ◽  
Single Species ◽  
Commensal Bacteria ◽  
Individual Species ◽  
Human Gut ◽  
Content Type ◽  
Clostridioides Difficile ◽  
Gut Pathogen

ABSTRACT Interactions of commensal bacteria within the gut microbiota and with invading pathogens are critical in determining the outcome of an infection. While murine studies have been valuable, we lack in vitro models to monitor community responses to pathogens at a single-species level. We have developed a multispecies community of nine representative gut species cultured together as a mixed biofilm and tracked numbers of individual species over time using a quantitative PCR (qPCR)-based approach. Introduction of the major nosocomial gut pathogen, Clostridioides difficile, to this community resulted in increased adhesion of commensals and inhibition of C. difficile multiplication. Interestingly, we observed an increase in individual Bacteroides species accompanying the inhibition of C. difficile. Furthermore, Bacteroides dorei reduced C. difficile growth within biofilms, suggesting a role for Bacteroides spp. in prevention of C. difficile colonization. We report here an in vitro tool with excellent applications for investigating bacterial interactions within a complex community. IMPORTANCE Studying interactions between bacterial species that reside in the human gut is crucial for gaining a better insight into how they provide protection from pathogen colonization. In vitro models of multispecies bacterial communities wherein behaviors of single species can be accurately tracked are key to such studies. Here, we have developed a synthetic, trackable, gut microbiota community which reduces growth of the human gut pathogen Clostridioides difficile. We report that Bacteroides spp. within this community respond by multiplying in the presence of this pathogen, resulting in reduction of C. difficile growth. Defined in vitro communities that can be tailored to include different species are well suited to functional genomic approaches and are valuable tools for understanding interbacterial interactions.

scholarly journals In VitroandIn VivoCharacterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase

2016 ◽  
Vol 60 (8) ◽  
pp. 4830-4839 ◽  
Author(s):  
Christopher M. Tan ◽  
Charles J. Gill ◽  
Jin Wu ◽  
Nathalie Toussaint ◽  
Jingjun Yin ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Antibacterial Agents ◽  
Cell Activity ◽  
Dna Gyrase ◽  
Topoisomerase Iv ◽  
Bacterial Dna ◽  
Whole Cell ◽  
Content Type

ABSTRACTOxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, andin vivocharacterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV fromStaphylococcus aureusandEscherichia coliand displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergencein vitroat concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activityin vitroandin vivo.

scholarly journals Ursodeoxycholic Acid (UDCA) Mitigates the Host Inflammatory Response during Clostridioides difficile Infection by Altering Gut Bile Acids

2020 ◽  
Vol 88 (6) ◽  
Author(s):  
Jenessa A. Winston ◽  
Alissa J. Rivera ◽  
Jingwei Cai ◽  
Rajani Thanissery ◽  
Stephanie A. Montgomery ◽  
...  
Keyword(s):  
Immune Response ◽  
Bile Acid ◽  
Inflammatory Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Colonization Resistance ◽  
Content Type ◽  
Clostridioides Difficile

ABSTRACT Clostridioides difficile infection (CDI) is associated with increasing morbidity and mortality posing an urgent threat to public health. Recurrence of CDI after successful treatment with antibiotics is high, thus necessitating discovery of novel therapeutics against this enteric pathogen. Administration of the secondary bile acid ursodeoxycholic acid (UDCA; ursodiol) inhibits the life cycles of various strains of C. difficile in vitro, suggesting that the FDA-approved formulation of UDCA, known as ursodiol, may be able to restore colonization resistance against C. difficile in vivo. However, the mechanism(s) by which ursodiol is able to restore colonization resistance against C. difficile remains unknown. Here, we confirmed that ursodiol inhibits C. difficile R20291 spore germination and outgrowth, growth, and toxin activity in a dose-dependent manner in vitro. In a murine model of CDI, exogenous administration of ursodiol resulted in significant alterations in the bile acid metabolome with little to no changes in gut microbial community structure. Ursodiol pretreatment resulted in attenuation of CDI pathogenesis early in the course of disease, which coincided with alterations in the cecal and colonic inflammatory transcriptome, bile acid-activated receptors nuclear farnesoid X receptor (FXR) and transmembrane G-protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-κB. Although ursodiol pretreatment did not result in a consistent decrease in the C. difficile life cycle in vivo, it was able to attenuate an overly robust inflammatory response that is detrimental to the host during CDI. Ursodiol remains a viable nonantibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid-activated receptors FXR and TGR5 represents a new potential treatment strategy for patients with CDI.

scholarly journals Molecular insights into the genome dynamics and interactions between core and acquired genomes ofVibrio cholerae

2020 ◽  
Vol 117 (38) ◽  
pp. 23762-23773
Author(s):  
Archana Pant ◽  
Satyabrata Bag ◽  
Bipasa Saha ◽  
Jyoti Verma ◽  
Pawan Kumar ◽  
...  
Keyword(s):  
Bacterial Species ◽  
Bacterial Genome ◽  
Genomic Islands ◽  
Host Bacterium ◽  
Metabolic Functions ◽  
Bipartite Genome ◽  
Ctx Prophage ◽  
Integrative Conjugative Elements

Bacterial species are hosts to horizontally acquired mobile genetic elements (MGEs), which encode virulence, toxin, antimicrobial resistance, and other metabolic functions. The bipartite genome ofVibrio choleraeharbors sporadic and conserved MGEs that contribute in the disease development and survival of the pathogens. For a comprehensive understanding of dynamics of MGEs in the bacterial genome, we engineered the genome ofV. choleraeand examined in vitro and in vivo stability of genomic islands (GIs), integrative conjugative elements (ICEs), and prophages. Recombinant vectors carrying the integration module of these GIs, ICE and CTXΦ, helped us to understand the efficiency of integrations of MGEs in theV. choleraechromosome. We have deleted more than 250 acquired genes from 6 different loci in theV. choleraechromosome and showed contribution of CTX prophage in the essentiality of SOS response master regulator LexA, which is otherwise not essential for viability in other bacteria, includingEscherichia coli. In addition, we observed that the core genome-encoded RecA helps CTXΦ to bypassV. choleraeimmunity and allow it to replicate in the host bacterium in the presence of similar prophage in the chromosome. Finally, our proteomics analysis reveals the importance of MGEs in modulating the levels of cellular proteome. This study engineered the genome ofV. choleraeto remove all of the GIs, ICEs, and prophages and revealed important interactions between core and acquired genomes.

scholarly journals In VitroandIn VivoActivities of Zinc Linolenate, a Selective Antibacterial Agent againstHelicobacter pylori

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Yanqiang Huang ◽  
Xudong Hang ◽  
Xueqing Jiang ◽  
Liping Zeng ◽  
Jia Jia ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Therapeutic Potential ◽  
Combined Therapy ◽  
Peptic Ulcers ◽  
Current Standard ◽  
Gastric Diseases ◽  
Content Type ◽  
H Pylori

ABSTRACTHelicobacter pyloriis a major global pathogen, and its infection represents a key factor in the etiology of various gastric diseases, including gastritis, peptic ulcers, and gastric carcinoma. The efficacy of current standard treatment forH. pyloriinfection including two broad-spectrum antibiotics is compromised by toxicity toward the gut microbiota and the development of drug resistance, which will likely only be resolved through novel and selective antibacterial strategies. Here, we synthesized a small molecule, zinc linolenate (ZnLla), and investigated its therapeutic potential for the treatment ofH. pyloriinfection. ZnLla showed effective antibacterial activity against standard strains and drug-resistant clinical isolates ofH. pyloriin vitrowith no development of resistance during continuous serial passaging. The mechanisms of ZnLla action againstH. pyloriinvolved the disruption of bacterial cell membranes and generation of reactive oxygen species. In mouse models of multidrug-resistantH. pyloriinfection, ZnLla showedin vivokilling efficacy comparable and superior to the triple therapy approach when use as a monotherapy and a combined therapy with omeprazole, respectively. Moreover, ZnLla treatment induces negligible toxicity against normal tissues and causes minimal effects on both the diversity and composition of the murine gut microbiota. Thus, the high degree of selectivity of ZnLla forH. pyloriprovides an attractive candidate for novel targeted anti-H. pyloritreatment.

scholarly journals Intestinal IgA Regulates Expression of a Fructan Polysaccharide Utilization Locus in Colonizing Gut Commensal Bacteroides thetaiotaomicron

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Payal Joglekar ◽  
Hua Ding ◽  
Pablo Canales-Herrerias ◽  
Pankaj Jay Pasricha ◽  
Justin L. Sonnenburg ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Ex Vivo ◽  
Microbial Colonization ◽  
Bacteroides Thetaiotaomicron ◽  
Content Type ◽  
Microbial Utilization ◽  
Polysaccharide Utilization Locus ◽  
The Impact

ABSTRACT Gut-derived immunoglobulin A (IgA) is the most abundant antibody secreted in the gut that shapes gut microbiota composition and functionality. However, most of the microbial antigens targeted by gut IgA remain unknown, and the functional effects of IgA targeting these antigens are currently understudied. This study provides a framework for identifying and characterizing gut microbiota antigens targeted by gut IgA. We developed a small intestinal ex vivo culture assay to harvest lamina propria IgA from gnotobiotic mice, with the aim of identifying antigenic targets in a model human gut commensal, Bacteroides thetaiotaomicron VPI-5482. Colonization by B. thetaiotaomicron induced a microbe-specific IgA response that was reactive against diverse antigens, including capsular polysaccharides, lipopolysaccharides, and proteins. IgA against microbial protein antigens targeted membrane and secreted proteins with diverse functionalities, including an IgA specific against proteins of the polysaccharide utilization locus (PUL) that are necessary for utilization of fructan, which is an important dietary polysaccharide. Further analyses demonstrated that the presence of dietary fructan increased the production of fructan PUL-specific IgA, which then downregulated the expression of fructan PUL in B. thetaiotaomicron, both in vivo and in vitro. Since the expression of fructan PUL has been associated with the ability of B. thetaiotaomicron to colonize the gut in the presence of dietary fructans, our work suggests a novel role for gut IgA in regulating microbial colonization by modulating their metabolism. IMPORTANCE Given the significant impact that gut microbes have on our health, it is essential to identify key host and environmental factors that shape this diverse community. While many studies have highlighted the impact of diet on gut microbiota, little is known about how the host regulates this critical diet-microbiota interaction. In our present study, we discovered that gut IgA targeted a protein complex involved in the utilization of an important dietary polysaccharide: fructan. While the presence of dietary fructans was previously thought to allow unrestricted growth of fructan-utilizing bacteria, our work shows that gut IgA, by targeting proteins responsible for fructan utilization, provides the host with tools that can restrict the microbial utilization of such polysaccharides, thereby controlling their growth.

scholarly journals Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors

2014 ◽  
Vol 58 (6) ◽  
pp. 3312-3326 ◽  
Author(s):  
B. K. Kishore Reddy ◽  
Sudhir Landge ◽  
Sudha Ravishankar ◽  
Vikas Patil ◽  
Vikas Shinde ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Present Report ◽  
Kinetic Studies ◽  
Antimycobacterial Activity ◽  
Type I ◽  
Pantothenate Kinase ◽  
Content Type ◽  
Rate Limiting Step

ABSTRACTPantothenate kinase (PanK) catalyzes the phosphorylation of pantothenate, the first committed and rate-limiting step toward coenzyme A (CoA) biosynthesis. In our earlier reports, we had established that the type I isoform encoded by thecoaAgene is an essential pantothenate kinase inMycobacterium tuberculosis, and this vital information was then exploited to screen large libraries for identification of mechanistically different classes of PanK inhibitors. The present report summarizes the synthesis and expansion efforts to understand the structure-activity relationships leading to the optimization of enzyme inhibition along with antimycobacterial activity. Additionally, we report the progression of two distinct classes of inhibitors, the triazoles, which are ATP competitors, and the biaryl acetic acids, with a mixed mode of inhibition. Cocrystallization studies provided evidence of these inhibitors binding to the enzyme. This was further substantiated with the biaryl acids having MIC against the wild-typeM. tuberculosisstrain and the subsequent establishment of a target link with an upshift in MIC in a strain overexpressing PanK. On the other hand, the ATP competitors had cellular activity only in aM. tuberculosisknockdown strain with reduced PanK expression levels. Additionally,in vitroandin vivosurvival kinetic studies performed with aM. tuberculosisPanK (MtPanK) knockdown strain indicated that the target levels have to be significantly reduced to bring in growth inhibition. The dual approaches employed here thus established the poor vulnerability of PanK inM. tuberculosis.

scholarly journals Hydroxylamine and Carboxymethoxylamine Can Inhibit Toxoplasma gondii Growth through an Aspartate Aminotransferase-Independent Pathway

2020 ◽  
Vol 64 (3) ◽  
Author(s):  
Jixu Li ◽  
Huanping Guo ◽  
Eloiza May Galon ◽  
Yang Gao ◽  
Seung-Hun Lee ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Drug Targets ◽  
Protozoan Parasite ◽  
Cell Types ◽  
Lytic Cycle ◽  
Type I ◽  
Content Type ◽  
Mechanism Of Inhibition

ABSTRACT Toxoplasma gondii is an obligate intracellular protozoan parasite and a successful parasitic pathogen in diverse organisms and host cell types. Hydroxylamine (HYD) and carboxymethoxylamine (CAR) have been reported as inhibitors of aspartate aminotransferases (AATs) and interfere with the proliferation in Plasmodium falciparum. Therefore, AATs are suggested as drug targets against Plasmodium. The T. gondii genome encodes only one predicted AAT in both T. gondii type I strain RH and type II strain PLK. However, the effects of HYD and CAR, as well as their relationship with AAT, on T. gondii remain unclear. In this study, we found that HYD and CAR impaired the lytic cycle of T. gondii in vitro, including the inhibition of invasion or reinvasion, intracellular replication, and egress. Importantly, HYD and CAR could control acute toxoplasmosis in vivo. Further studies showed that HYD and CAR could inhibit the transamination activity of rTgAAT in vitro. However, our results confirmed that deficiency of AAT in both RH and PLK did not reduce the virulence in mice, although the growth ability of the parasites was affected in vitro. HYD and CAR could still inhibit the growth of AAT-deficient parasites. These findings indicated that HYD and CAR inhibition of T. gondii growth and control of toxoplasmosis can occur in an AAT-independent pathway. Overall, further studies focusing on the elucidation of the mechanism of inhibition are warranted. Our study hints at new substrates of HYD and CAR as potential drug targets to inhibit T. gondii growth.

scholarly journals USA300 and USA500 Clonal Lineages of Staphylococcus aureus Do Not Produce a Capsular Polysaccharide Due to Conserved Mutations in the cap5 Locus

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Susan Boyle-Vavra ◽  
Xue Li ◽  
Md Tauqeer Alam ◽  
Timothy D. Read ◽  
Julia Sieth ◽  
...  
Keyword(s):  
United States ◽  
Staphylococcus Aureus ◽  
Capsular Polysaccharide ◽  
The United States ◽  
Whole Genome Sequence ◽  
Content Type ◽  
Capsule Production ◽  
Usa300 Strain

ABSTRACTThe surface capsular polysaccharide (CP) is a virulence factor that has been used as an antigen in several successful vaccines against bacterial pathogens. A vaccine has not yet been licensed againstStaphylococcus aureus, although two multicomponent vaccines that contain CP antigens are in clinical trials. In this study, we evaluated CP production in USA300 methicillin-resistantS. aureus(MRSA) isolates that have become the predominant community-associated MRSA clones in the United States. We found that all 167 USA300 MRSA and 50 USA300 methicillin-susceptibleS. aureus(MSSA) isolates were CP negative (CP−). Moreover, all 16 USA500 isolates, which have been postulated to be the progenitor lineage of USA300, were also CP−. Whole-genome sequence analysis of 146 CP−USA300 MRSA isolates revealed they all carry acap5locus with 4 conserved mutations compared with strain Newman. Genetic complementation experiments revealed that three of these mutations (in thecap5promoter,cap5Dnucleotide 994, andcap5Enucleotide 223) ablated CP production in USA300 and that Cap5E75 Asp, located in the coenzyme-binding domain, is essential for capsule production. All but three USA300 MSSA isolates had the same fourcap5mutations found in USA300 MRSA isolates. Most isolates with a USA500 pulsotype carried three of these four USA300-specific mutations, suggesting the fourth mutation occurred in the USA300 lineage. Phylogenetic analysis of thecaploci of our USA300 isolates as well as publicly available genomes from 41 other sequence types revealed that the USA300-specificcap5mutations arose sequentially inS. aureusin a common ancestor of USA300 and USA500 isolates.IMPORTANCEThe USA300 MRSA clone emerged as a community-associated pathogen in the United States nearly 20 years ago. Since then, it has rapidly disseminated and now causes health care-associated infections. This study shows that the CP-negative (CP−) phenotype has persisted among USA300 isolates and is a universal and characteristic trait of this highly successful MRSA lineage. It is important to note that a vaccine consisting solely of CP antigens would not likely demonstrate high efficacy in the U.S. population, where about half of MRSA isolates comprise USA300. Moreover, conversion of a USA300 strain to a CP-positive (CP+) phenotype is unlikelyin vivoorin vitrosince it would require the reversion of 3 mutations. We have also established that USA300 MSSA isolates and USA500 isolates are CP−and provide new insight into the evolution of the USA300 and USA500 lineages.

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