Combating highly resistant emerging pathogen Mycobacterium abscessus and Mycobacterium tuberculosis with novel salicylanilide esters and carbamates
Combating highly resistant emerging pathogen Mycobacterium abscessus and Mycobacterium tuberculosis with novel salicylanilide esters and carbamates
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DOI：
10.1016/j.ejmech.2015.07.001
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发表时间：
2015-08-28
影响因子：
6.7
通讯作者：
Bosze, Szilvia
中科院分区：
文献类型：
--
作者：
Baranyai, Zsuzsa;Kratky, Martin;Bosze, Szilvia
在分枝杆菌属中，已经描述了100多个物种，并且定期报告新的物种。在一周内形成菌落的物种被归类为快速生长者，那些需要更长时间（长达三个月）的物种是大多数致病性缓慢生长者。最近，新出现的物种已经被确定，以延长名单，所有快速增长。其中，分枝杆菌也是一种细胞内病原体，并且它是最耐化疗的快速生长分枝杆菌。此外，耐多药结核分枝杆菌感染的病例也在增加。因此，迫切需要找到针对这些威胁菌株的新的活性分子。在前人研究的基础上，设计、合成了一系列水杨酰苯胺类化合物、水杨酰苯胺5-氯吡嗪酸酯和水杨酰苯胺氨基甲酸酯。评价了化合物对M. Escherichia L.结核H（37）Rv、多药耐药M. tuberculosis MDR A8、M.结核MDR 9449/2006和极端耐药普拉哈131（XDR）菌株。所有衍生物均表现出显着的活性，最低抑菌浓度（MIC）在低微摩尔范围内。8种水杨酰苯胺氨基甲酸酯和2种水杨酰苯胺酯对M.其MIC为0.2 - 2.1 μ M，因此比环丙沙星和庆大霉素更有效。这一发现是潜在的有希望的，特别是，作为M。这种植物对化疗有很强的抵抗力。M.结核病H（37）Rv的抑制MIC为0.2 μ M，11种化合物的MIC低于异烟肼。水杨酰苯胺酯类和氨基甲酸酯类药物对MDR和XDR M也有效。MIC>= 1.0 μ M的结核病菌株。对人MonoMac-6细胞的体外细胞毒性（IC_（50））和选择性指数（SI）进行了测定，结果表明水杨酰苯胺衍生物的活性优于4-苯甲酰基苯胺衍生物。母体水杨酰苯胺的酯键或氨基甲酸酯键的形成主要保留或提高了抗分枝杆菌的效力，具有中等的选择性。(C)2015年Elsevier Masson SAS。All rights reserved.
In the Mycobacterium genus over one hundred species are already described and new ones are periodically reported. Species that form colonies in a week are classified as rapid growers, those requiring longer periods (up to three months) are the mostly pathogenic slow growers. More recently, new emerging species have been identified to lengthen the list, all rapid growers. Of these, Mycobacterium abscessus is also an intracellular pathogen and it is the most chemotherapy-resistant rapid-growing mycobacterium. In addition, the cases of multidrug-resistant Mycobacterium tuberculosis infection are also increasing. Therefore there is an urgent need to find new active molecules against these threatening strains. Based on previous results, a series of salicylanilides, salicylanilide 5-chloropyrazinoates and carbamates was designed, synthesized and characterised. The compounds were evaluated for their in vitro activity on M. abscessus, susceptible M. tuberculosis H(37)Rv, multidrug-resistant (MDR) M. tuberculosis MDR A8, M. tuberculosis MDR 9449/2006 and on the extremely-resistant Praha 131 (XDR) strains. All derivatives exhibited a significant activity with minimum inhibitory concentrations (MICs) in the low micromolar range. Eight salicylanilide carbamates and two salicylanilide esters exhibited an excellent in vitro activity on M. abscessus with MICs from 0.2 to 2.1 mu M, thus being more effective than ciprofloxacin and gentamicin. This finding is potentially promising, particularly, as M. abscessus is a threateningly chemotherapy-resistant species. M. tuberculosis H(37)Rv was inhibited with MICs from 0.2 mu M, and eleven compounds have lower MICs than isoniazid. Salicylanilide esters and carbamates were found that they were effective also on MDR and XDR M. tuberculosis strains with MICs >= 1.0 mu M. The in vitro cytotoxicity (IC50) was also determined on human MonoMac-6 cells, and selectivity index (SI) of the compounds was established.In general, salicylanilide derivatives substituted by halogens on both salicyl and aniline rings showed better activity, than 4-benzoylaniline derivatives. The ester or carbamate bond formation of parent salicylanilides mostly retained or improved antimycobacterial potency with moderate selectivity. (C) 2015 Elsevier Masson SAS. All rights reserved.