<p>AmpR Increases the Virulence of Carbapenem-Resistant <em>Klebsiella pneumoniae</em> by Regulating the Initial Step of Capsule Synthesis</p>

Abstract

Background: Non-hypermucoviscous carbapenem-resistant Klebsiella pneumoniae with enhanced virulence lacking hvKP-specific virulence factors is uncommon, and the virulence mechanisms of this organism are not understood. Methods: Following a retrospective study of carbapenem-resistant K. pneumoniae based on core genome multilocus sequence typing (cgMLST), isolates that caused high mortality were investigated with a genome-wide association study (GWAS), proteome analysis and an animal model. Results: The subclone of sequence type 11 (ST11) K. pneumoniae, which belongs to complex type 3176 (CT3176) and K-locus 47 (KL47), was highlighted due to the high mortality of infected patients. GWAS analysis showed that transcriptional regulatory gene ampR was associated with the CT3176 isolates. In a mouse model, the mortality, bacterial load and pathological changes of mice infected with ampR-carrying isolates were distinct from those infected with ampR-null isolates. The ampR gene that enhances the virulence of the non-hypermucoviscous KL47 strain was unable to enhance the virulence of hypermucoviscous KL1 strain. Proteome analysis showed that the expression of WcaJ in the ampR + isolates was significantly higher than that in the ampR − isolates. Quantification of capsular polysaccharide confirmed that more capsule polysaccharide was produced by ampR + and ampR-complementary strains compared to ampR − strains. It is suggested that the enhancement of the initial stage of capsule synthesis may be the cause of the enhanced virulence of these non-hypermucoviscous ST11 carbapenem-resistant K. pneumoniae isolates. Conclusion: Non-hypermucoviscous ST11 carbapenem-resistant K. pneumoniae with enhanced virulence warrants continued surveillance and investigation.

Bacterial virulence regulation through soluble peptidoglycan fragments sensing and response: knowledge gaps and therapeutic potential

“…In this same paper, the capacity of AmpR to regulate biofilm formation and type 3 fimbrial gene expression was also demonstrated, with obvious impacts on adhesion to host tissues. More recently, the presence of AmpR in the genome of certain strains of carbapenem-resistant K. pneumoniae was reported to be associated with increased production of capsule and virulence too (Hennequin et al 2012 , Zhang et al 2020 ).…”

From Klebsiella pneumoniae Colonization to Dissemination: An Overview of Studies Implementing Murine Models

“…For instance, a mutant deficient in FimK, a pilus regulator involved in capsule production, produces significatively less capsule than the wild-type strain and is attenuated in virulence in murine intrapulmonary models compared to the parental strain, suggesting that the capsule protects bacteria from the host immune response in the lungs [103]. More recently, Zhang et al used an intrapulmonary in vivo model to identify AmpR, a regulator of the WcaJ enzyme that initiates capsule synthesis, as essential for the virulence of both hypermucoviscous and non-hypermucoviscous K. pneumoniae strains [111]. In addition, ∆rcsB and ∆rmpA mutant strains had lung colo-nization levels that were about 4-log lower than that of the parental strain KPPR1S at 24 h post-infection in an intranasal model of pneumonia in mice, and a ∆rmpC strain was also attenuated by nearly 2 logs [87].…”

A cyclic adenosine monophosphate response element-binding protein inhibitor enhances the antibacterial activity of polymyxin B by inhibiting the ATP hydrolyzation activity of CrrB

“…Proteome analysis of K. pneumoniae ATCC13883 cells treated with PB (2 µg/ml) alone or the combination of 666-15 (50 µg/ml) and PB (2 µg/ml) was performed according to our previous report ( Zhang et al, 2020 ). Briefly, a 100 ml culture (OD 600 = 0.8) was centrifuged (12,000 rpm, 3 min) and washed with precooled PBS.…”