Dataset Information

A Genomic Approach To Identify Klebsiella pneumoniae and Acinetobacter baumannii Strains with Enhanced Competitive Fitness in the Lungs during Multistrain Pneumonia.

ABSTRACT: Microbial competition is most often studied at the genus or species level, but interstrain competition has been less thoroughly examined. Klebsiella pneumoniae is an important pathogen in the context of hospital-acquired pneumonia, and a better understanding of strain competition in the lungs could explain why some strains of this bacterium are more frequently isolated from pneumonia patients than others. We developed a barcode-free method called "StrainSeq" to simultaneously track the abundances of 10 K. pneumoniae strains in a murine pneumonia model. We demonstrate that one strain (KPPR1) repeatedly achieved a marked numerical dominance at 20?h postinoculation during pneumonia but did not exhibit a similar level of dominance in in vitro mixed-growth experiments. The emergence of a single dominant strain was also observed with a second respiratory pathogen, Acinetobacter baumannii, indicating that the phenomenon was not unique to K. pneumoniae When KPPR1 was removed from the inoculum, a second strain emerged to achieve high numbers in the lungs, and when KPPR1 was introduced into the lungs 1 h after the other nine strains, it no longer exhibited a dominant phenotype. Our findings indicate that certain strains of K. pneumoniae have the ability to outcompete others in the pulmonary environment and cause severe pneumonia and that a similar phenomenon occurs with A. baumannii In the context of the pulmonary microbiome, interstrain competitive fitness may be another factor that influences the success and spread of certain lineages of these hospital-acquired respiratory pathogens.

SUBMITTER: Agard MJ

PROVIDER: S-EPMC6529660 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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A Genomic Approach To Identify Klebsiella pneumoniae and Acinetobacter baumannii Strains with Enhanced Competitive Fitness in the Lungs during Multistrain Pneumonia.

Agard Mallory J MJ Ozer Egon A EA Morris Andrew R AR Piseaux Raul R Hauser Alan R AR

Infection and immunity 20190521 6

Microbial competition is most often studied at the genus or species level, but interstrain competition has been less thoroughly examined. <i>Klebsiella pneumoniae</i> is an important pathogen in the context of hospital-acquired pneumonia, and a better understanding of strain competition in the lungs could explain why some strains of this bacterium are more frequently isolated from pneumonia patients than others. We developed a barcode-free method called "StrainSeq" to simultaneously track the ab ...[more]

PMID: 30936161

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Project description:Antibiotic-resistant infections caused by gram-negative bacteria are a major healthcare concern. Repurposing drugs circumvents the time and money limitations associated with developing new antimicrobial agents needed to combat these antibiotic-resistant infections. Here we identified the off-patent antifungal agent, ciclopirox, as a candidate to repurpose for antibiotic use. To test the efficacy of ciclopirox against antibiotic-resistant pathogens, we used a curated collection of Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates that are representative of known antibiotic resistance phenotypes. We found that ciclopirox, at 5-15 µg/ml concentrations, inhibited bacterial growth regardless of the antibiotic resistance status. At these same concentrations, ciclopirox reduced growth of Pseudomonas aeruginosa clinical isolates, but some of these pathogens required higher ciclopirox concentrations to completely block growth. To determine how ciclopirox inhibits bacterial growth, we performed an overexpression screen in E. coli. This screen revealed that galE, which encodes UDP-glucose 4-epimerase, rescued bacterial growth at otherwise restrictive ciclopirox concentrations. We found that ciclopirox does not inhibit epimerization of UDP-galactose by purified E. coli GalE; however, ?galU, ?galE, ?rfaI, or ?rfaB mutant strains all have lower ciclopirox minimum inhibitory concentrations than the parent strain. The galU, galE, rfaI, and rfaB genes all encode enzymes that use UDP-galactose or UDP-glucose for galactose metabolism and lipopolysaccharide (LPS) biosynthesis. Indeed, we found that ciclopirox altered LPS composition of an E. coli clinical isolate. Taken together, our data demonstrate that ciclopirox affects galactose metabolism and LPS biosynthesis, two pathways important for bacterial growth and virulence. The lack of any reported fungal resistance to ciclopirox in over twenty years of use in the clinic, its excellent safety profiles, novel target(s), and efficacy, make ciclopirox a promising potential antimicrobial agent to use against multidrug-resistant problematic gram-negative pathogens.

Dataset Information

A Genomic Approach To Identify Klebsiella pneumoniae and Acinetobacter baumannii Strains with Enhanced Competitive Fitness in the Lungs during Multistrain Pneumonia.

Publications

A Genomic Approach To Identify Klebsiella pneumoniae and Acinetobacter baumannii Strains with Enhanced Competitive Fitness in the Lungs during Multistrain Pneumonia.

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