Mechanistic Studies and In Vivo Efficacy of an Oxadiazole-Containing Antibiotic.
Mechanistic Studies and In Vivo Efficacy of an Oxadiazole-Containing Antibiotic.
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DOI：
10.1021/acs.jmedchem.1c02034
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发表时间：
2022-05-12
影响因子：
7.3
通讯作者：
Sintim, Herman O.
中科院分区：
文献类型：
--
作者：
Naclerio, George A.;Abutaleb, Nader S.;Onyedibe, Kenneth, I;Karanja, Caroline;Eldesouky, Hassan E.;Liang, Hsin-Wen;Dieterly, Alexandra;Aryal, Uma K.;Lyle, Tiffany;Seleem, Mohamed N.;Sintim, Herman O.
耐甲氧西林金黄色葡萄球菌（MRSA）感染仍然难以治疗，尽管许多FDA批准的抗生素可用。因此，仍然需要新的复合支架来治疗MRSA。含恶二唑的化合物HSGN-94已被证明可减少S.金黄色葡萄球菌，但解释LTA生物合成抑制的机制仍然没有表征。在这里，我们报告HSGN-94通过利用全球蛋白质组学，基于活性的蛋白质分析和脂质分析，通过多反应监测（MRM）抑制LTA生物合成的机制的阐明。我们的数据表明，HSGN-94通过直接结合PgcA和下调PgsA来抑制LTA生物合成。我们进一步表明，HSGN-94减少了皮肤感染（小鼠）中的MRSA负荷，并减少了MRSA感染伤口中的促炎细胞因子。总的来说，HSGN-94值得进一步考虑作为葡萄球菌感染的潜在药物。
Methicillin-resistant Staphylococcus aureus (MRSA) infections are still difficult to treat, despite the availability of many FDA-approved antibiotics. Thus, new compound scaffolds are still needed to treat MRSA. The oxadiazole-containing compound, HSGN-94, has been shown to reduce lipoteichoic acid (LTA) in S. aureus, but the mechanism that accounts for LTA biosynthesis inhibition remains uncharacterized. Here, we report the elucidation of the mechanism by which HSGN-94 inhibits LTA biosynthesis via utilization of global proteomics, activity-based protein profiling, and lipid analysis via multiple reaction monitoring (MRM). Our data suggest that HSGN-94 inhibits LTA biosynthesis via direct binding to PgcA and downregulation of PgsA. We further show that HSGN-94 reduces the MRSA load in skin infection (mouse) and decreases pro-inflammatory cytokines in MRSA infected wounds. Collectively, HSGN-94 merits further consideration as a potential drug for staphylococcal infections.
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影响因子：
2.7
作者：
Abutaleb NS;Elhassanny AEM;Flaherty DP;Seleem MN
通讯作者：
Seleem MN
影响因子：
3.7
作者：
Montgomery CP;Daniels MD;Zhao F;Spellberg B;Chong AS;Daum RS
通讯作者：
Daum RS
影响因子：
6.5
作者：
Brauweiler, Anne M.;Goleva, Elena;Leung, Donald Y. M.
通讯作者：
Leung, Donald Y. M.
影响因子：
4.4
作者：
Chaudhuri RR;Allen AG;Owen PJ;Shalom G;Stone K;Harrison M;Burgis TA;Lockyer M;Garcia-Lara J;Foster SJ;Pleasance SJ;Peters SE;Maskell DJ;Charles IG
通讯作者：
Charles IG
影响因子：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias