Research Article: Host adaptation and convergent evolution increases antibiotic resistance without loss of virulence in a major human pathogen

Date Published: March 15, 2019

Publisher: Public Library of Science

Author(s): Alicia Fajardo-Lubián, Nouri L. Ben Zakour, Alex Agyekum, Qin Qi, Jonathan R. Iredell, David Skurnik.


As human population density and antibiotic exposure increase, specialised bacterial subtypes have begun to emerge. Arising among species that are common commensals and infrequent pathogens, antibiotic-resistant ‘high-risk clones’ have evolved to better survive in the modern human. Here, we show that the major matrix porin (OmpK35) of Klebsiella pneumoniae is not required in the mammalian host for colonisation, pathogenesis, nor for antibiotic resistance, and that it is commonly absent in pathogenic isolates. This is found in association with, but apparently independent of, a highly specific change in the co-regulated partner porin, the osmoporin (OmpK36), which provides enhanced antibiotic resistance without significant loss of fitness in the mammalian host. These features are common in well-described ‘high-risk clones’ of K. pneumoniae, as well as in unrelated members of this species and similar adaptations are found in other members of the Enterobacteriaceae that share this lifestyle. Available sequence data indicate evolutionary convergence, with implications for the spread of lethal antibiotic-resistant pathogens in humans.

Partial Text

Host adaptation and niche specialisation are well described in bacteria. As human population density rises, commensals and pathogens among the Enterobacteriaceae are transmitted directly from human to human and increasingly exposed to antibiotics. K. pneumoniae is now a common cause of healthcare-associated infections and is one of the most important agents of human sepsis [1]. High morbidity and mortality are associated with acquired antibiotic resistance, most importantly by horizontal transfer of genes encoding extended-spectrum β-lactamases (ESBL) [2] and plasmid-mediated AmpC β-lactamases (pAmpC) [3]. Carbapenem antibiotics have been effective against such isolates for decades, but resistance to these antibiotics is increasingly common in turn [4] and in February 2017, carbapenem resistant Enterobacteriaceae were listed among the highest (‘critical’) research priorities by the World Health Organisation. Acquired genes encoding efficient carbapenem hydrolysing enzymes [5] typically require phenotypic augmentation by permeability reduction to be clinically relevant in the Enterobacteriaceae. Indeed, clinically significant carbapenem resistance may even be seen with the less specialised AmpC or ESBL enzymes in strains with sufficiently reduced outer membrane permeability [6,7].

β-lactam antibiotics are among the most commonly prescribed for severe infections [85,86] and the emergence of β-lactam resistance in K. pneumoniae has become a global health threat [87,88]. In general, E. coli and K. pneumoniae carrying transmissible β-lactam resistance genes have predictable and normally distributed β-lactam MICs [21] but carbapenem MICs in K. pneumoniae are bimodally distributed with higher MICs correlating with OmpK36 defects [21]. OmpK36 loss or mutation is not uncommonly reported in highly resistant clinical isolates producing KPC, ESBL and AmpC β-lactamases [20,89,90].