Antibacterial activity of the novel semisynthetic lantibiotic NVB333 in vitro and in experimental infection models
Antibacterial activity of the novel semisynthetic lantibiotic NVB333 in vitro and in experimental infection models
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DOI：
10.1038/ja.2016.47
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发表时间：
2016-12-01
影响因子：
3.3
通讯作者：
Dawson, Michael J.
中科院分区：
文献类型：
--
作者：
Boakes, Steven;Weiss, William J.;Dawson, Michael J.
NVB 333是一种新型的半合成羊毛硫抗生素，其衍生自3，5-二氯苄胺与脱氧阿克加定B的C-末端的酰胺偶联。NVB 333的体外活性包括针对临床相关病原体的功效，所述病原体包括耐甲氧西林金黄色葡萄球菌和耐万古霉素肠球菌。NVB 333与其他测试的抗生素没有交叉耐药性，并且耐药性发展的倾向非常低。静脉内给药后，NVB 333在小鼠血浆中具有高暴露量，并且在小鼠感染模型中与万古霉素相比显示出总体改善的体内活性，尽管MIC值适中。在大腿感染模型中，对几种S.金黄色葡萄球菌，包括耐甲氧西林的S.金黄色葡萄球菌（MRSA）和万古霉素中间体S.金黄色葡萄球菌（VISA）菌株，以及针对粪肠球菌UNT 126 -3。浓度曲线下面积（AUC）/MIC显示为对S.金黄色葡萄球菌UNT 103 -3，AUC/MIC为138（未校正蛋白结合），实现静态效应。NVB 333在播散性感染模型中也是有效的，其中它赋予MRSA菌株ATCC 33591的完全存活。NVB 333在静脉内给药后显示相当适度的肺渗透（肺中的AUC为血浆AUC的2-3%），但由于非常高的血浆暴露，在肺中实现了化合物的治疗水平。在支气管肺泡感染模型中，证明了对MRSA菌株（UNT 084 -3）的疗效至少与万古霉素相当。NVB 333令人印象深刻的体内功效和强耐药性预后使该化合物成为开发用于治疗全身性革兰氏阳性感染的有趣候选物。
NVB333 is a novel semisynthetic lantibiotic derived from the amide coupling of 3,5-dichlorobenzylamine to the C-terminal of deoxyactagardine B. The in vitro activity of NVB333 includes efficacy against clinically relevant pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. NVB333 shows no cross-resistance with other antibiotics tested and a very low propensity for resistance development. After intravenous dosing NVB333 has high exposure in mouse plasma and shows generally improved in vivo activity compared with vancomycin in mouse infection models despite modest MIC values. In thigh infection models, promising efficacy was demonstrated against several strains of S. aureus including methicillin-resistant S. aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) strains, and against Enterococcus faecalis UNT126-3. Area under the concentration curve (AUC)/MIC was shown to be the best predictor of efficacy against S. aureus UNT103-3 with an AUC/MIC of 138 (uncorrected for protein binding) achieving a static effect. NVB333 was also effective in a disseminated infection model where it conferred complete survival from the MRSA strain ATCC 33591. NVB333 showed rather modest lung penetration after intravenous dosing (AUC in lung 2-3% of plasma AUC), but because of very high plasma exposure, therapeutic levels of compound were achieved in the lung. Efficacy at least equal to vancomycin was demonstrated against an MRSA strain (UNT084-3) in a bronchoalveolar infection model. The impressive in vivo efficacy of NVB333 and strong resistance prognosis makes this compound an interesting candidate for development for treating systemic Gram-positive infections.