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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Peptide deformylase in Staphylococcus aureus: resistance to inhibition is mediated by mutations in the formyltransferase gene.
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Peptide deformylase in Staphylococcus aureus: resistance to inhibition is mediated by mutations in the formyltransferase gene.

机译：金黄色葡萄球菌中的肽去甲酰基化酶：对抑制的抗性由甲酰基转移酶基因的突变介导。

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摘要

Peptide deformylase, a bacterial enzyme, represents a novel target for antibiotic discovery. Two deformylase homologs, defA and defB, were identified in Staphylococcus aureus. The defA homolog, located upstream of the transformylase gene, was identified by genomic analysis and was cloned from chromosomal DNA by PCR. A distinct homolog, defB, was cloned from an S. aureus genomic library by complementation of the arabinose-dependent phenotype of a P(BAD)-def Escherichia coli strain grown under arabinose-limiting conditions. Overexpression in E. coli of defB, but not defA, correlated to increased deformylase activity and decreased susceptibility to actinonin, a deformylase-specific inhibitor. The defB gene could not be disrupted in wild-type S. aureus, suggesting that this gene, which encodes a functional deformylase, is essential. In contrast, the defA gene could be inactivated; the function of this gene is unknown. Actinonin-resistant mutants grew slowly in vitro and did not show cross-resistance to other classes of antibiotics. When compared to the parent, an actinonin-resistant strain produced an attenuated infection in a murine abscess model, indicating that this strain also has a growth disadvantage in vivo. Sequence analysis of the actinonin-resistant mutants revealed that each harbors a loss-of-function mutation in the fmt gene. Susceptibility to actinonin was restored when the wild-type fmt gene was introduced into these mutant strains. An S. aureus Deltafmt strain was also resistant to actinonin, suggesting that a functional deformylase activity is not required in a strain that lacks formyltransferase activity. Accordingly, the defB gene could be disrupted in an fmt mutant.
机译：肽变形酶（一种细菌酶）代表了抗生素发现的新目标。在金黄色葡萄球菌中鉴定出两个去甲酰基酶同系物defA和defB。通过基因组分析鉴定了位于转化酶基因上游的defA同源物，并通过PCR从染色体DNA克隆。通过互补于在阿拉伯糖限制条件下生长的P（BAD）-def大肠杆菌菌株的阿拉伯糖依赖性表型，从金黄色葡萄球菌基因组文库中克隆了一个独特的同源物defB。 defB（而非defA）在大肠杆菌中的过量表达与甲酰化酶活性的增加和对甲酰化酶（一种甲酰化酶特异性抑制剂）的敏感性降低有关。 defB基因不能在野生型金黄色葡萄球菌中被破坏，这表明该基因编码功能性去甲酰基酶，是必不可少的。相反，defA基因可能被灭活。该基因的功能尚不清楚。耐肌动蛋白的突变体在体外生长缓慢，并且对其他种类的抗生素没有交叉耐药性。当与亲本相比时，耐肌动蛋白的菌株在鼠脓肿模型中产生了减毒感染，表明该菌株在体内也具有生长缺陷。耐放线肌动蛋白的突变体的序列分析表明，每个突变体在fmt基因中都存在功能丧失突变。将野生型fmt基因导入这些突变菌株后，肌动蛋白的敏感性得以恢复。金黄色葡萄球菌Deltafmt菌株也对肌动蛋白具有抗性，表明在缺乏甲酰基转移酶活性的菌株中不需要功能性甲氨酰化酶活性。因此，可以在fmt突变体中破坏defB基因。

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