Antimicrobial Action and Reversal of Resistance in MRSA by Difluorobenzamide Derivatives Targeted at FtsZ

被引:13
作者
Chai, Wern Chern [1 ]
Whittall, Jonathan J. [1 ]
Song, Di [2 ]
Polyak, Steven W. [1 ]
Ogunniyi, Abiodun D. [3 ]
Wang, Yinhu [2 ,4 ]
Bi, Fangchao [2 ]
Ma, Shutao [2 ]
Semple, Susan J. [1 ,5 ]
Venter, Henrietta [1 ]
机构
[1] Univ South Australia, Clin & Hlth Sci, Hlth & Biomed Innovat, Adelaide, SA 5000, Australia
[2] Shandong Univ, Cheeloo Coll Med, Sch Pharmaceut Sci, Key Lab Chem Biol,Minist Educ,Dept Med Chem, Jinan 250012, Peoples R China
[3] Univ Adelaide, Australia Ctr Antimicrobial Resistance Ecol, Sch Anim & Vet Sci, Roseworthy Campus, Roseworthy, SA 5371, Australia
[4] Liaocheng Univ, Sch Pharm, Liaocheng 25200, Shandong, Peoples R China
[5] Univ South Australia, Qual Use Med & Pharm Res Ctr, Clin & Hlth Sci, Adelaide, SA 5000, Australia
来源
ANTIBIOTICS-BASEL | 2020年 / 9卷 / 12期
基金
美国国家科学基金会; 英国医学研究理事会;
关键词
antimicrobial resistance; antimicrobial development; reversing resistance; FtsZ inhibitors; 3-methoxybenzamide; methicillin resistant Staphylococcus aureus; DIVISION INHIBITOR PC190723; PROTEIN FTSZ; BACTERIAL; PRODRUG; DESIGN; EFFICACY; THERAPY; SYNERGY; TUBULIN; CONFERS;
D O I
10.3390/antibiotics9120873
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
The bacterial cell division protein, FtsZ, has been identified as a target for antimicrobial development. Derivatives of 3-methoxybenzamide have shown promising activities as FtsZ inhibitors in Gram-positive bacteria. We sought to characterise the activity of five difluorobenzamide derivatives with non-heterocyclic substituents attached through the 3-oxygen. These compounds exhibited antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA), with an isopentyloxy-substituted compound showing modest activity against vancomycin resistant Enterococcus faecium (VRE). The compounds were able to reverse resistance to oxacillin in highly resistant clinical MRSA strains at concentrations far below their MICs. Three of the compounds inhibited an Escherichia coli strain lacking the AcrAB components of a drug efflux pump, which suggests the lack of Gram-negative activity can partly be attributed to efflux. The compounds inhibited cell division by targeting S. aureus FtsZ, producing a dose-dependent increase in GTPase rate which increased the rate of FtsZ polymerization and stabilized the FtsZ polymers. These compounds did not affect the polymerization of mammalian tubulin and did not display haemolytic activity or cytotoxicity. These derivatives are therefore promising compounds for further development as antimicrobial agents or as resistance breakers to re-sensitive MRSA to beta-lactam antibiotics.
引用
收藏
页码:1 / 22
页数:22
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