pH-dependent beta-lactam resistance in Klebsiella pneumoniae is mediated by paralogous class B PBPs and the class A PBP, PBP1b

Klebsiella pneumoniae is a leading cause of global deaths due to antibiotic resistance. Of particular concern, is the rapid expansion of resistance to beta-lactam antibiotics within K. pneumoniae lineages. The environmental factors that influence pathogen physiology and, subsequently, antibiotic resistance remain poorly understood. Here we demonstrate that physiologically-relevant reductions in pH increased antibiotic resistance as much as 64-fold, with the most dramatic increases observed for beta-lactams that inhibit cell division. We identified two genes that contribute to acid-dependent beta-lactam resistance, the class A PBP, PBP1b, and the paralogous class B PBP, PBP3 _PARA . Loss of either gene increases K. pneumoniae susceptibility to beta-lactams at low pH. Our data supports previous work from our group and others indicating that functional redundancy among cell wall synthesis enzymes allows for specialization and ensures robust cell wall synthesis across a range of environmental conditions.