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Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant Klebsiella pneumoniae Strains Identifies Genes for Antibiotic Resistance and Virulence.

ABSTRACT: Global increases in the use of carbapenems have resulted in several strains of Gram-negative bacteria acquiring carbapenem resistance, thereby limiting treatment options. Klebsiella pneumoniae is a common carbapenem-resistant pathogenic bacterium that is widely studied to identify novel antibiotic resistance mechanisms and drug targets. Antibiotic-resistant clinical isolates generally harbor many genetic alterations, and the identification of responsible mutations would provide insights into the molecular mechanisms of antibiotic resistance. We propose a method to prioritize mutated genes responsible for antibiotic resistance on the basis of expression changes in their local subnetworks, hypothesizing that mutated genes that show significant expression changes among the corresponding functionally associated genes are more likely to be involved in the carbapenem resistance. For network-based gene prioritization, we developed KlebNet (www.inetbio.org/klebnet), a genome-scale cofunctional network of K. pneumoniae genes. Using KlebNet, we reconstructed the functional modules for carbapenem resistance and virulence and identified the functional association between antibiotic resistance and virulence. Using complementation assays with the top candidate genes, we were able to validate a novel gene that negatively regulated carbapenem resistance and four novel genes that positively regulated virulence in Galleria mellonella larvae. Therefore, our study demonstrated the feasibility of network-based identification of genes required for antibiotic resistance and virulence of human-pathogenic bacteria.IMPORTANCE Klebsiella pneumoniae is a major bacterial pathogen that causes pneumonia and urinary tract infections in human. K. pneumoniae infections are treated with carbapenem, but carbapenem-resistant K. pneumoniae has been spreading worldwide. We are able to identify antimicrobial-resistant genes among mutated genes of the antibiotic-resistant clinical isolates. However, they usually harbor many mutated genes, including those that cause weak or neutral functional effects. Therefore, we need to prioritize the mutated genes to identify the more likely candidates for the follow-up functional analysis. For this study, we present a functional network of K. pneumoniae genes and propose a network-based method of prioritizing the mutated genes of the resistant clinical isolates. We also reconstructed the network-based functional modules for carbapenem resistance and virulence and retrieved the functional association between antibiotic resistance and virulence. This study demonstrated the feasibility of network-based analysis of clinical genomics data for the study of K. pneumoniae infection.

SUBMITTER: Lee M

PROVIDER: S-EPMC6589436 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant Klebsiella pneumoniae Strains Identifies Genes for Antibiotic Resistance and Virulence.

Lee Muyoung M Pinto Naina Adren NA Kim Chan Yeong CY Yang Sunmo S D'Souza Roshan R Yong Dongeun D Lee Insuk I

mSystems 20190521 4

Global increases in the use of carbapenems have resulted in several strains of Gram-negative bacteria acquiring carbapenem resistance, thereby limiting treatment options. <i>Klebsiella pneumoniae</i> is a common carbapenem-resistant pathogenic bacterium that is widely studied to identify novel antibiotic resistance mechanisms and drug targets. Antibiotic-resistant clinical isolates generally harbor many genetic alterations, and the identification of responsible mutations would provide insights i ...[more]

PMID: 31117026

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Project description:Carbapenem-resistant Klebsiella pneumonia (CRKP) infections has become a concerning threat. However, knowledge regarding the characteristics of intestinal CRKP isolates is limited. This study aimed to investigate and compare the clinical, virulence and molecular epidemiological characteristics of intestinal colonization and extraintestinal infections CRKP strains. The clinical characteristics were investigated retrospectively. Polymerase chain reaction was used to investigate the capsular serotype, virulence genes and carbapenemase genes. Capsular polysaccharide quantification assay, serum resistance assay, biofilm formation assay, and infection model of Galleria mellonella larvae were performed to compare the virulence and pathogenicity. Besides, multilocus-sequence-typing (MLST) and pulsed-field-gel-electrophoresis (PFGE) were conducted to explore the homology of intestinal CRKP isolates. A total of 54 intestinal CRKP isolates were included. The main capsular serotypes were K14, K64, and K19. C-reactive protein and the proportion of ICU isolation of the infection group were significantly higher than that of the colonization group (P < 0.05). The carrier rates of various virulence genes of CRKP in the infection group were mostly higher than those in the colonization group, wherein the carrier rates of peg-344 and rmpA were significantly different (P < 0.05). There was no significant difference in capsular polysaccharides, antiserum ability, biofilm formation ability between the two group (P > 0.05), but the lethality of the infection group to Galleria mellonella was significantly higher than that of the colonization group (P < 0.05). The MLST categorized the 54 isolates into 13 different sequence types. PFGE revealed that homology among the 54 CRKP strains was <80%. This study suggested that the CRKP strains in the infection group had higher virulence than those in the colonization group. The development of CRKP isolates colonizing in the intestine should be addressed in future clinical surveillance.

Project description:Introduction:Klebsiella pneumoniae is one of the most important infectious agents in neonates. There are "classic" and hypervirulent strains of K. pneumoniae. The "classic" non-virulent strain of K. pneumoniae, producing extended-spectrum beta-lactamases (ESBLs), is associated with nosocomial infections. Hypervirulent K. pneumoniae strains are associated with invasive infections in previously healthy adult people, and most of them exhibit antimicrobial susceptibility. The role of virulent strains of K. pneumoniae (including hv-KP) in neonatal infections is unknown. The aim of the study was the assessment of the impact of virulence factors and antibiotic resistance of K. pneumoniae strains on clinical features and outcomes of neonatal infection. Materials and Methods: Two groups of infants were enrolled. The first group consisted of 10 neonates with sepsis caused by K. pneumoniae. The second group consisted of 10 neonates with urinary tract infection (UTI) caused by K. pneumoniae. We investigated the susceptibility of K. pneumoniae isolates to antibiotics, the ability of the microorganism to produce ESBL, and virulence factors, including the rmpA gene, aerobactin, and colibactin genes. In neonates with sepsis, we investigated K. pneumoniae isolates, which was taken from the blood, in neonates with UTI-from the urine. Results: In neonates with sepsis testing of K. pneumoniae isolates for ESBL production was positive in 60% of cases, in neonates with UTI-in 40% of cases. All blood and urine ESBL producing K. pneumoniae isolates were resistant to ampicillins, including protected ones, and third-generation cephalosporins. At the same time, these isolates were sensitive to meropenem, amikacin, and ciprofloxacin. The rmpA gene was detected in four blood, and three urine K. pneumoniae isolates. In neonates with sepsis rmpA gene in two cases was detected in ESBL-producing K. pneumoniae isolates. They were infants with meningitis, and both cases were fatal. In the group of infants with UTI, the rmpA gene was detected only in K. pneumoniae isolates not producing ESBL. Aerobactin and colibactin genes were detected in two neonates with sepsis and in three neonates with UTI. In all cases, aerobactin and colibactin genes were detected only in rmpA-positive K. pneumoniae isolates. Out of three fatal outcomes, two cases were caused by hv-KP producing ESBL. Conclusion: The prevalence of virulent strains of K. pneumoniae among neonates with sepsis and other neonatal infection is higher than we think. The most severe forms of neonatal sepsis with an unfavorable outcome in our study were due to virulent strains of K. pneumoniae.

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Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant Klebsiella pneumoniae Strains Identifies Genes for Antibiotic Resistance and Virulence.

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Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant Klebsiella pneumoniae Strains Identifies Genes for Antibiotic Resistance and Virulence.

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