O'Neill A J, Bostock J M, Moita A Morais, Chopra I
Antimicrobial Research Centre and Division of Microbiology, University of Leeds, Leeds LS2 9JT, UK.
J Antimicrob Chemother. 2002 Dec;50(6):839-48. doi: 10.1093/jac/dkf248.
The antimicrobial properties of cephalosporin P1, an antibiotic structurally related to fusidic acid, were examined. Cephalosporin P1 exhibited potent activity against methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus and vancomycin-intermediate S. aureus. Mutants of S. aureus resistant to cephalosporin P1 arose with a frequency of 1.6 x 10(-6) for selections at 4 x MIC, a frequency similar to that for fusidic acid. The mutations conferred cross-resistance to fusidic acid and mapped in fusA, the gene encoding elongation factor G. Cross-resistance between cephalosporin P1 and fusidic acid also occurred for S. aureus fusA mutants selected with fusidic acid, and in fusidic acid-resistant clinical isolates. Plasmid pUB101, which mediates resistance to fusidic acid in S. aureus, also conferred resistance to cephalosporin P1. Escherichia coli was intrinsically resistant to both fusidic acid and cephalosporin P1, but deletion of the AcrAB efflux pump resulted in susceptibility to both antibiotics. Although complete cross-resistance between fusidic acid and cephalosporin P1 was demonstrated, the nature and location of fusA mutations in S. aureus when cephalosporin P1 was the selective agent frequently differed from those selected with fusidic acid. This may reflect differences in the interaction of the two antibiotics with the translational apparatus, which results in the selection of separate mutation classes for each antibiotic. Furthermore, in three of 14 mutants selected with fusidic acid, resistance was attributed to mutations lying outside fusA. In contrast, mutations in 10 mutants selected with cephalosporin P1 were all located in fusA.
对与夫西地酸结构相关的抗生素头孢菌素P1的抗菌特性进行了研究。头孢菌素P1对甲氧西林敏感金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌和万古霉素中介金黄色葡萄球菌表现出强效活性。在4倍最低抑菌浓度（MIC）下筛选时，对头孢菌素P1耐药的金黄色葡萄球菌突变体出现频率为1.6×10⁻⁶，这一频率与夫西地酸相似。这些突变赋予了对夫西地酸的交叉耐药性，且定位在fusA基因，即编码延伸因子G的基因中。在用夫西地酸筛选的金黄色葡萄球菌fusA突变体以及耐夫西地酸临床分离株中，头孢菌素P1和夫西地酸之间也出现了交叉耐药性。介导金黄色葡萄球菌对夫西地酸耐药的质粒pUB101也赋予了对头孢菌素P1的耐药性。大肠杆菌对夫西地酸和头孢菌素P1均固有耐药，但缺失AcrAB外排泵后对这两种抗生素均敏感。尽管已证明夫西地酸和头孢菌素P1之间存在完全交叉耐药性，但当以头孢菌素P1作为选择剂时，金黄色葡萄球菌中fusA突变的性质和位置常常与用夫西地酸选择的不同。这可能反映了两种抗生素与翻译装置相互作用的差异，导致为每种抗生素选择了不同的突变类别。此外，在用夫西地酸筛选的14个突变体中的3个中，耐药性归因于fusA基因外的突变。相比之下，用头孢菌素P1筛选的10个突变体中的突变均位于fusA基因中。
