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A Klebsiella pneumoniae antibiotic resistance mechanism that subdues host defences and promotes virulence.

ABSTRACT: Klebsiella pneumoniae is an important cause of multidrug-resistant infections worldwide. Recent studies highlight the emergence of multidrug-resistant K. pneumoniae strains which show resistance to colistin, a last-line antibiotic, arising from mutational inactivation of the mgrB regulatory gene. However, the precise molecular resistance mechanisms of mgrB-associated colistin resistance and its impact on virulence remain unclear. Here, we constructed an mgrB gene K. pneumoniae mutant and performed characterisation of its lipid A structure, polymyxin and antimicrobial peptide resistance, virulence and inflammatory responses upon infection. Our data reveal that mgrB mutation induces PhoPQ-governed lipid A remodelling which confers not only resistance to polymyxins, but also enhances K. pneumoniae virulence by decreasing antimicrobial peptide susceptibility and attenuating early host defence response activation. Overall, our findings have important implications for patient management and antimicrobial stewardship, while also stressing antibiotic resistance development is not inexorably linked with subdued bacterial fitness and virulence.

SUBMITTER: Kidd TJ

PROVIDER: S-EPMC5376759 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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A Klebsiella pneumoniae antibiotic resistance mechanism that subdues host defences and promotes virulence.

Kidd Timothy J TJ Mills Grant G Sá-Pessoa Joana J Dumigan Amy A Frank Christian G CG Insua José L JL Ingram Rebecca R Hobley Laura L Bengoechea José A JA

EMBO molecular medicine 20170401 4

Klebsiella pneumoniae is an important cause of multidrug-resistant infections worldwide. Recent studies highlight the emergence of multidrug-resistant K. pneumoniae strains which show resistance to colistin, a last-line antibiotic, arising from mutational inactivation of the mgrB regulatory gene. However, the precise molecular resistance mechanisms of mgrB-associated colistin resistance and its impact on virulence remain unclear. Here, we constructed an mgrB ge ...[more]

PMID: 28202493

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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.

Project description:Carbapenemase-producing Klebsiella pneumoniae (CP-Kpn) are a major concern for nosocomial infections. We previously reported an intensive care unit (ICU) outbreak of CP-Kpn. This study investigated the transmission pattern and genetic characteristic of CP-Kpn in the hospital during the outbreak period. Whole-genome sequencing was retrospectively performed on 173 CP-Kpn isolates. Pairwise single-nucleotide polymorphism (SNP) distances were calculated to determine SNP thresholds for clustering. Plasmids and mobile genome elements (MGEs) were identified through short- and long-read sequencing. Strains were classified into three groups, sequence type 11 (ST11) (86.12%), ST15 (9.83%), and other ST. An SNP threshold of 16 revealed a 66.47% clustering rate. ICU admission and meropenem use proportions were significantly higher in clustered patients than in unique patients. MGE distribution was consistent with the phylogenetic tree. Of the isolates, 53.18% were CP-Kpn with hypervirulence genes. We identified five plasmids carrying virulence genes, and four of them have not been previously reported. Clonal transmission was the main cause of CP-Kpn infections in the hospital. Multidrug resistance genes and MGE variations were correlated with clustering. Finally, four novel plasmids carrying virulence genes were identified. The findings highlight the control of CR-Kpn transmission through prevention measures to reduce nosocomial infections. IMPORTANCE In this study, we combined genomic and epidemiological analyses and defined an optimal cutoff value for SNP difference that could be used to aid investigation in tertiary hospital in China. We revealed clonal transmission was the main cause of CP-Kpn infections in the hospital and identified four novel plasmids carrying virulence genes. Our results strongly suggested that dominant CP K. pneumoniae strains lead to outbreaks and described different evolutionary patterns of plasmids carrying multidrug resistance and virulence genes.

Project description:BACKGROUND:Endemic presence of Klebsiella pneumoniae resistant to carbapenem in Italy has been due principally to the clonal expansion of CC258 isolates; however, recent studies suggest an ongoing epidemiological change in this geographical area. METHODS:50?K. pneumoniae strains, 25 carbapenem-resistant (CR-Kp) and 25 susceptible (CS-Kp), collected from march 2014 to march 2016 at the Laboratory of Bacteriology of the Paolo Giaccone Polyclinic University hospital of Palermo, Italy, were characterized for antibiotic susceptibility and fully sequenced by next generation sequencing (NGS) for the in silico analysis of resistome, virulome, multi-locus sequence typing (MLST) and core single nucleotide polymorphism (SNP) genotypes RESULTS: MLST in silico analysis of CR-Kp showed that 52% of isolates belonged to CC258, followed by ST395 (12%), ST307 (12%), ST392 (8%), ST348 (8%), ST405 (4%) and ST101 (4%). In the CS-Kp group, the most represented isolate was ST405 (20%), followed by ST392 and ST15 (12%), ST395, ST307 and ST1727 (8%). The in silico ?-lactamase analysis of the CR-Kp group showed that the most detected gene was blaSHV (100%), followed by blaTEM (92%), blaKPC (88%), blaOXA (88%) and blaCTX-M (32%). The virulome analysis detected mrk operon in all studied isolates, and wzi-2 was found in three CR-Kp isolates (12%). Furthermore, the distribution of virulence genes encoding for the yersiniabactin system, its receptor fyuA and the aerobactin system did not show significant distribution differences between CR-Kp and CS-Kp, whereas the Klebsiella ferrous iron uptake system (kfuA, kfuB and kfuC genes), the two-component system kvgAS and the microcin E495 were significantly (p?<?0.05) prevalent in the CS-Kp group compared to the CR-Kp group. Core SNP genotyping, correlating with the MLST data, allowed greater strain tracking and discrimination than MLST analysis. CONCLUSIONS:Our data support the idea that an epidemiological change is ongoing in the Palermo area (Sicily, Italy). In addition, our analysis revealed the co-existence of antibiotic resistance and virulence factors in CR-Kp isolates; this characteristic should be considered for future genomic surveillance studies.

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A Klebsiella pneumoniae antibiotic resistance mechanism that subdues host defences and promotes virulence.

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A <i>Klebsiella pneumoniae</i> antibiotic resistance mechanism that subdues host defences and promotes virulence.

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