Lee Yong Heon, Helmann John D
Department of Microbiology, Cornell University, Ithaca, New York, USA.
Department of Microbiology, Cornell University, Ithaca, New York, USA
Antimicrob Agents Chemother. 2013 Sep;57(9):4267-4275. doi: 10.1128/AAC.00794-13. Epub 2013 Jun 24.
Undecaprenyl pyrophosphate synthase (UppS) catalyzes the formation of the C lipid carrier (UPP) that is essential for bacterial peptidoglycan biosynthesis. We selected here a vancomycin (VAN)-resistant derivative of W168 that contains a single-point mutation in the ribosome-binding site of the gene designated Genetic reconstruction experiments demonstrate that the allele is sufficient to confer low-level VAN resistance and causes reduced UppS translation. The decreased level of UppS renders slightly more susceptible to many late-acting cell wall antibiotics, including β-lactams, but significantly more resistant to fosfomycin and d-cycloserine, antibiotics that interfere with the very early steps of cell wall synthesis. We further show that the allele leads to slightly elevated expression of the σ regulon, possibly helping to compensate for the stress caused by a decrease in UPP levels. Notably, the mutation increases resistance to VAN, fosfomycin, and d-cycloserine in wild-type cells, but this effect is greatly reduced or eliminated in a mutant 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.
十一异戊烯基焦磷酸合酶（UppS）催化C脂质载体（UPP）的形成，而UPP对于细菌肽聚糖的生物合成至关重要。我们在此选择了W168的一种耐万古霉素（VAN）衍生物，其在名为的基因的核糖体结合位点含有一个单点突变。基因重建实验表明，等位基因足以赋予低水平的VAN抗性并导致UppS翻译减少。UppS水平的降低使对许多后期作用的细胞壁抗生素（包括β-内酰胺类）略微更敏感，但对磷霉素和d-环丝氨酸（干扰细胞壁合成非常早期步骤的抗生素）的抗性显著增强。我们进一步表明，等位基因导致σ调节子的表达略有升高，可能有助于补偿UPP水平降低所造成的压力。值得注意的是，突变增加了野生型细胞对VAN、磷霉素和d-环丝氨酸的抗性，但在突变背景下这种效应大大降低或消除。我们的研究结果表明，尽管UppS是一个有吸引力的抗菌靶点，但对UppS功能的不完全抑制可能导致对某些细胞壁活性抗生素的抗性增加。
