Response of methicillin-resistant Staphylococcus aureus to amicoumacin A.
Response of methicillin-resistant Staphylococcus aureus to amicoumacin A.
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DOI：
10.1371/journal.pone.0034037
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Nakano MM
中科院分区：
文献类型：
--
作者：
Lama A;Pané-Farré J;Chon T;Wiersma AM;Sit CS;Vederas JC;Hecker M;Nakano MM
Amicoumacin A对耐甲氧西林金黄色葡萄球菌（MRSA）表现出较强的抗菌活性，因此我们试图揭示其作用机制。金黄色葡萄球菌对amicoumacin A反应的全基因组转录组分析显示，指定细胞过程的基因转录发生改变，包括细胞包膜更新、跨膜运输、毒力、代谢和一般应激反应。诱导程度最高的基因是lrgA，它编码一种抗holin样产物，这种产物在经历Δψ崩溃的细胞中被诱导。与LrgA调节小鼠水解酶活性的观点一致，在amicoumacin A存在下生长的COL表现出自溶性降低，这主要是由于水解酶活性降低引起的。为了进一步了解amicoumacin A的作用机制，采用串联传代法对COL野生型和amicoumacin A耐药突变体进行了全基因组比较。在ksgA（编码RNA二甲基转移酶）、fusA（延伸因子G）、dnaG（引物酶）、lacD（塔格糖1,6-二磷酸醛缩酶）和SACOL0611（一种假定的糖基转移酶）中发现了产生密码子替换的单点突变。EF-G中引起amicoumacin A抗性和fususidic酸抗性的密码子替换位于不同的结构域，不会产生交叉抗性。综上所述，这些结果表明amicoumacin A可能引起细胞膜的扰动并导致能量耗散。在耐药菌株中，细胞代谢率（包括蛋白质合成和DNA复制）的降低可能允许细胞补偿膜功能障碍，从而提高细胞存活率。
Amicoumacin A exhibits strong antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), hence we sought to uncover its mechanism of action. Genome-wide transcriptome analysis of S. aureus COL in response to amicoumacin A showed alteration in transcription of genes specifying several cellular processes including cell envelope turnover, cross-membrane transport, virulence, metabolism, and general stress response. The most highly induced gene was lrgA, encoding an antiholin-like product, which is induced in cells undergoing a collapse of Δψ. Consistent with the notion that LrgA modulates murein hydrolase activity, COL grown in the presence of amicoumacin A showed reduced autolysis, which was primarily caused by lower hydrolase activity. To gain further insight into the mechanism of action of amicoumacin A, a whole genome comparison of wild-type COL and amicoumacin A-resistant mutants isolated by a serial passage method was carried out. Single point mutations generating codon substitutions were uncovered in ksgA (encoding RNA dimethyltransferase), fusA (elongation factor G), dnaG (primase), lacD (tagatose 1,6-bisphosphate aldolase), and SACOL0611 (a putative glycosyl transferase). The codon substitutions in EF-G that cause amicoumacin A resistance and fusidic acid resistance reside in separate domains and do not bring about cross resistance. Taken together, these results suggest that amicoumacin A might cause perturbation of the cell membrane and lead to energy dissipation. Decreased rates of cellular metabolism including protein synthesis and DNA replication in resistant strains might allow cells to compensate for membrane dysfunction and thus increase cell survivability.
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DOI：
10.1038/newbio233012a0
发表时间：
1971-01-01
期刊：
NATURE-NEW BIOLOGY
影响因子：
--
作者：
HELSER, TL;DAVIES, JE;DAHLBERG, JE
通讯作者：
DAHLBERG, JE
DOI：
10.1007/s004380051001
发表时间：
1999-04-01
期刊：
MOLECULAR AND GENERAL GENETICS
影响因子：
--
作者：
Gertz, S;Engelmann, S;Hecker, M
通讯作者：
Hecker, M
影响因子：
4.8
作者：
Fuda, C;Suvorov, M;Mobashery, S
通讯作者：
Mobashery, S
影响因子：
3.1
作者：
Houston, Patrick;Rowe, Sarah E.;O'Gara, James P.
通讯作者：
O'Gara, James P.
影响因子：
3.2
作者：
Groicher, KH;Firek, BA;Bayles, KW
通讯作者：
Bayles, KW