replaces virulence with carbapenem resistance via porin loss.

Abstract

Pathogenicspecies are of increasing clinical concern due to the multidrug-resistant nature of these bacteria, including resistance to carbapenem antibiotics. Our understanding ofvirulence is limited, hindering the development of new prophylactics and therapeutics targeting infections caused byspecies. In this study, we assessed the virulence of contemporary clinicalisolates in a mouse model of intraperitoneal infection and used comparative genomics to identify genes promoting virulence. Through mutagenesis and complementation studies, we found two porin-encoding genes,and, to be required forvirulence. These porins imported clinically relevant carbapenems into the bacteria, and thus loss of OmpC and OmpD desensitizedto the antibiotics. Our genomic analyses suggest porin-related genes are frequently mutated in, perhaps due to the selective pressure of antibiotic therapy during infection. Despite the importance of OmpC and OmpD during infection of immunocompetent hosts, we found the two porins to be dispensable for virulence in a neutropenic mouse model. Moreover, porin loss provided a fitness advantage during carbapenem treatment in an ex vivo human whole blood model of bacteremia. Our data provide experimental evidence of pathogenicspecies gaining antibiotic resistance via loss of porins and argue antibiotic therapy during infection of immunocompromised patients is a conducive environment for the selection of porin mutations enhancing the multidrug-resistant profile of these pathogens.