Dataset Information

Down-Regulation of Flagellar, Fimbriae, and Pili Proteins in Carbapenem-Resistant Klebsiella pneumoniae (NDM-4) Clinical Isolates: A Novel Linkage to Drug Resistance.

ABSTRACT: The emergence and spread of carbapenem-resistant Klebsiella pneumoniae infections have worsened the current situation worldwide, in which totally drug-resistant strains (bad bugs) are becoming increasingly prominent. Bacterial biofilms enable bacteria to tolerate higher doses of antibiotics and other stresses, which may lead to the drug resistance. In the present study, we performed proteomics on the carbapenem-resistant NDM-4-producing K. pneumoniae clinical isolate under meropenem stress. Liquid chromatography coupled with mass spectrometry (LC-MS/MS) analysis revealed that 69 proteins were down-regulated (?0.42-fold change) under meropenem exposure. Within the identified down-regulated proteome (69 proteins), we found a group of 13 proteins involved in flagellar, fimbriae, and pili formation and their related functions. Further, systems biology approaches were employed to reveal their networking pathways. We suggest that these down-regulated proteins and their interactive partners cumulatively contribute to the emergence of a biofilm-like state and the survival of bacteria under drug pressure, which could reveal novel mechanisms or pathways involved in drug resistance. These down-regulated proteins and their pathways might be used as targets for the development of novel therapeutics against antimicrobial-resistant (AMR) infections.

SUBMITTER: Sharma D

PROVIDER: S-EPMC6928051 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Down-Regulation of Flagellar, Fimbriae, and Pili Proteins in Carbapenem-Resistant Klebsiella pneumoniae (NDM-4) Clinical Isolates: A Novel Linkage to Drug Resistance.

Sharma Divakar D Garg Anjali A Kumar Manish M Rashid Faraz F Khan Asad U AU

Frontiers in microbiology 20191217

The emergence and spread of carbapenem-resistant Klebsiella pneumoniae infections have worsened the current situation worldwide, in which totally drug-resistant strains (bad bugs) are becoming increasingly prominent. Bacterial biofilms enable bacteria to tolerate higher doses of antibiotics and other stresses, which may lead to the drug resistance. In the present study, we performed proteomics on the carbapenem-resistant NDM-4-producing K. pneumoniae clinical isolate under meropene ...[more]

PMID: 31921045

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Project description:The emergence and dissemination of carbapenemases, bacterial enzymes able to inactivate most β-lactam antibiotics, in Enterobacteriaceae is of increasing concern. The concurrent spread of resistance against colistin, an antibiotic of last resort, further compounds this challenge further. Whole-genome sequencing (WGS) can play a significant role in the rapid and accurate detection/characterization of existing and emergent resistance determinants, an essential aspect of public health surveillance and response activities to combat the spread of antimicrobial resistant bacteria. In the current study, WGS data was used to characterize the genomic content of antimicrobial resistance genes, including those encoding carbapenemases, in 10 multidrug-resistant Klebsiella pneumoniae isolates from Pakistan. These clinical isolates represented five sequence types: ST11 (n = 3 isolates), ST14 (n = 3), ST15 (n = 1), ST101 (n = 2), and ST307 (n = 1). Resistance profiles against 25 clinically-relevant antimicrobials were determined by broth microdilution; resistant phenotypes were observed for at least 15 of the 25 antibiotics tested in all isolates except one. Specifically, 8/10 isolates were carbapenem-resistant and 7/10 isolates were colistin-resistant. The blaNDM-1 and blaOXA-48 carbapenemase genes were present in 7/10 and 5/10 isolates, respectively; including 2 isolates carrying both genes. No plasmid-mediated determinants for colistin resistance (e.g. mcr) were detected, but disruptions and mutations in chromosomal loci (i.e. mgrB and pmrB) previously reported to confer colistin resistance were observed. A blaOXA-48-carrying IncL/M-type plasmid was found in all blaOXA-48-positive isolates. The application of WGS to molecular epidemiology and surveillance studies, as exemplified here, will provide both a more complete understanding of the global distribution of MDR isolates and a robust surveillance tool useful for detecting emerging threats to public health.

Project description:Objective:The emergence of carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-hvKp) strains poses a significant public threat, and effective antimicrobial therapy is urgently needed. Recent studies indicated that apramycin is a potent antibiotic with good activity against a range of multi-drug resistant pathogens. In this study, we evaluated the in vitro activity of apramycin against clinical CR-hvKp along with carbapenem-resistant non-hvKp (CR-non-hvKp) isolates. Methods:Broth microdilution method was used to evaluate the in vitro activities of apramycin, gentamicin, amikacin, imipenem, meropenem, doripenem, ertapenem and other comparator "last-resort" antimicrobial agents, including ceftazidime-avibactam, colistin and tigecycline, against eighty-four CR-hvKp and forty CR-non-hvKp isolates collected from three Chinese hospitals. Multilocus Sequence typing (MLST), molecular capsule typing (wzi sequencing) and antimicrobial resistance genes were examined by PCR and Sanger sequencing. Pulsed-field gel electrophoresis and next generation sequencing were conducted on selected isolates. Results:Among the 84 CR-hvKp isolates, 97.6, 100, 97.6, and 100% were resistant to imipenem, meropenem, doripenem and ertapenem, respectively. Apramycin demonstrated an MIC50/MIC90 of 4/8 ?g/mL against the CR-hvKp isolates. In contrast, the MIC50/MIC90 for amikacin and gentamicin were >64/>64 ?g/mL. All CR-hvKp isolates were susceptible to ceftazidime-avibactam, colistin and tigecycline with the MIC50/MIC90 values of 0.5/1, 0.25/0.5, 1/1, respectively. For CR-non-hvKp, The MIC50/90 values for apramycin, gentamicin and amikacin were 2/8, >64/>64, and >64/>64 ?g/mL, respectively. There were no statistical significance in the resistance rates of antimicrobial agents between CR-hvKp and CR-non-hvKp groups (p > 0.05). Genetic analysis revealed that all CR-hvKp isolates harbored bla KPC-2, and 94% (n = 79) belong to the ST11 high-risk clone. 93.6% (44/47) of amikacin or gentamicin resistant strains carried 16S rRNA methyltransferases gene rmtB. Conclusion:Apramycin demonstrated potent in vitro activity against CR-hvKp isolates, including those were resistant to amikacin or gentamicin. Further studies are needed to evaluate the applicability of apramycin to be used as a therapeutic antibiotic against CR-hvKp infections.

Dataset Information

Down-Regulation of Flagellar, Fimbriae, and Pili Proteins in Carbapenem-Resistant Klebsiella pneumoniae (NDM-4) Clinical Isolates: A Novel Linkage to Drug Resistance.

Publications

Down-Regulation of Flagellar, Fimbriae, and Pili Proteins in Carbapenem-Resistant <i>Klebsiella pneumoniae</i> (NDM-4) Clinical Isolates: A Novel Linkage to Drug Resistance.

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