Dissecting the role of QseC in mediating QseBC-PmrAB signaling in uropathogenic Escherichia coli

Abstract

Antibiotic resistance in bacteria is increasing globally. Urinary tract infections, which account for the majority of antibiotic prescriptions, are primarily caused by uropathogenic E. coli (UPEC). The latest report by the World Health Organization places carbapenem-resistant Enterobacteriaceae as the third most critical pathogens for which new therapies are required. In cases of carbapenem resistance, a last-resort class of antibiotics is colistin, for which bacteria can acquire resistance by modifying their cell wall. Typically these resistance factors are encoded on mobile elements that can be shared. However, the work here shows that transient antibiotic resistance may be intrinsic to the genome. In uropathogenic Escherichia coli, two signaling networks, polymyxin resistance A and B and quorum sensing E. coli B and C (PmrAB and QseBC respectively), interact to regulate physiological and virulence factors in response to environmental cues. These signaling networks are two-component systems that include a cognate membrane-embedded histidine kinase (sensor) and a cytoplasmic response regulator (responder). Signaling network cross-interactions are rarely reported. This work highlights the direct interaction between non-cognate partners PmrB and QseB. Additionally, the presence of PmrA and QseC are required for appropriate response to signal and the function of QseC as a reverse-phosphotransferase to regulate the level of activated QseB. This work not only reveals that all four components are necessary for normal response, but also that these four components interact in the presence of ferric iron to alter the outer membrane of uropathogenic E. coli and increase transient resistance to polymyxin B, a last line of defense drug. These data open up new avenues for targeting uropathogenic E. coli and identify new potential antimicrobial targets.