Reducing the Level of Undecaprenyl Pyrophosphate Synthase Has Complex Effects on Susceptibility to Cell Wall Antibiotics

Abstract

ABSTRACTUndecaprenyl pyrophosphate synthase (UppS) catalyzes the formation of the C55lipid carrier (UPP) that is essential for bacterial peptidoglycan biosynthesis. We selected here a vancomycin (VAN)-resistant derivative ofBacillus subtilisW168 that contains a single-point mutation in the ribosome-binding site of theuppSgene designateduppS1. Genetic reconstruction experiments demonstrate that theuppS1allele is sufficient to confer low-level VAN resistance and causes reduced UppS translation. The decreased level of UppS rendersB. subtilisslightly more susceptible to many late-acting cell wall antibiotics, including β-lactams, but significantly more resistant to fosfomycin andd-cycloserine, antibiotics that interfere with the very early steps of cell wall synthesis. We further show that theuppS1allele leads to slightly elevated expression of the σMregulon, possibly helping to compensate for the stress caused by a decrease in UPP levels. Notably, theuppS1mutation increases resistance to VAN, fosfomycin, andd-cycloserine in wild-type cells, but this effect is greatly reduced or eliminated in asigMmutant background. Our findings suggest that, although UppS is an attractive antibacterial target, incomplete inhibition of UppS function may lead to increased resistance to some cell wall-active antibiotics.