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.

Identification and Characterization of Two Klebsiella pneumoniae lpxL Lipid A Late Acyltransferases and Their Role in Virulence

“…2C). The lack of 2-hydroxymyristate was expected since LpxO modifies the C 14 transferred by LpxL2 to the 2= R-3-hydroxymyristoyl group (23,25). However, we did not anticipate the lack of 4-amino-4-deoxy-L-arabinose and palmitate.…”

“…1C) (23)(24)(25). We have demonstrated that these lipid A decorations provide resistance to APs (23)(24)(25) and K. pneumoniae mutants lacking them are attenuated for virulence in the mouse pneumonia model (23)(24)(25).…”

“…We have uncovered that K. pneumoniae lipid A could be decorated with palmitate, 4-amino-4-deoxy-L-arabinose, phosphoethanolamine, and 2-hydroxymyristate (C 14:OH ) (Fig. 1C) (23)(24)(25). The gene encoding the acyltransferase pagP is required for the addition of palmitate to lipid A, the pmrHFIJKLM (arnBCADTEF) loci (here referred to as the pmrF operon) are required for the synthesis and addition of aminoarabinose to lipid A, eptA (pmrC) is necessary for the modification of the lipid A with phosphoethanolamine, and lpxO is responsible for modification of the 2=-linked secondary acyl chain with a hydroxyl group at the 2 position (Fig.…”

“…The gene encoding the acyltransferase pagP is required for the addition of palmitate to lipid A, the pmrHFIJKLM (arnBCADTEF) loci (here referred to as the pmrF operon) are required for the synthesis and addition of aminoarabinose to lipid A, eptA (pmrC) is necessary for the modification of the lipid A with phosphoethanolamine, and lpxO is responsible for modification of the 2=-linked secondary acyl chain with a hydroxyl group at the 2 position (Fig. 1C) (23)(24)(25). We have demonstrated that these lipid A decorations provide resistance to APs (23)(24)(25) and K. pneumoniae mutants lacking them are attenuated for virulence in the mouse pneumonia model (23)(24)(25).…”

Antibacterial effects of the methanolic extract of Glycine Max (Soybean)

“…[1][2][3][4] Documented data revealed that pathogenic bacteria and especially Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Bacillus cereus (B. cereus), Pseudomonas aeruginosa (P. aeruginosa), Listeria monocytogenes (L. monocytogenes), Klebsiella pneumoniae (K. pneumoniae) and Salmonella typhi (S. typhi) exhibited the high levels of resistance against aminoglycosides, tetracyclines, lincosamides, macrolides, beta-lactams, quinolones, fluoroquinolone and cephems groups of antibiotics. [1][2][3][4][5][6][7][8] Therefore, therapeutic and pharmacological factories tried to use from novel sources for antimicrobial agents to produce strong antibiotic drugs. Application of medicinal plants for producing of antimicrobial agents had an ancient history.…”