Atypically Modified Carbapenem Antibiotics Display Improved Antimycobacterial Activity in the Absence of β-Lactamase Inhibitors.
Atypically Modified Carbapenem Antibiotics Display Improved Antimycobacterial Activity in the Absence of β-Lactamase Inhibitors.
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DOI：
10.1021/acsinfecdis.1c00185
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发表时间：
2021-08-13
影响因子：
5.3
通讯作者：
Buynak JD
中科院分区：
文献类型：
--
作者：
Gupta R;Al-Kharji NMSA;Alqurafi MA;Nguyen TQ;Chai W;Quan P;Malhotra R;Simcox BS;Mortimer P;Brammer Basta LA;Rohde KH;Buynak JD
商业碳青霉烯类抗生素被用于治疗多药耐药（MDR）和广泛耐药（XDR）结核病。与其他β-内酰胺类一样，碳青霉烯类是参与肽聚糖生物合成的丝氨酸d，d-转肽酶的不可逆抑制剂。除了d，d-转肽酶，分枝杆菌还利用非同源半胱氨酸l，d-转肽酶（Ldts）交联肽聚糖的茎肽，并且碳青霉烯类与Ldts形成长寿命酰基酶。商业碳青霉烯类是常见支架的C2修饰。本研究描述了碳青霉烯支架的一系列非典型C5α修饰的合成，对结核分枝杆菌（Mtb）和非结核分枝杆菌种属结核分枝杆菌（Mab）的微生物评价，以及重要分枝杆菌靶标Ldt LdtMt 2的酰化。对这些C5α-修饰的碳青霉烯类的体外评价显示，在不存在β-内酰胺酶抑制剂的情况下，Mtb的最小抑制浓度（MIC）上级优于美罗培南-克拉维汀，Mab的最小抑制浓度（MIC）优于美罗培南-阿维巴坦。时间-杀灭动力学测定显示，与美罗培南相比，用较低浓度的化合物10a对Mtb和Mab的杀灭更好（2- 4log降低）。尽管临床分离株对美罗培南的敏感性变化近100倍，但10a对所有Mtb和Mab菌株保持优异的活性。高分辨率质谱分析表明，10a酰化LdtMt 2的速率与美罗培南相当，但随后经历了前所未有的碳青霉烯断裂，导致一个酰基酶的质量为Δm = +86 Da。LdtMt 2酰基酶的非水解断裂的分歧提出了理由。观察到的活性说明了新型非典型碳青霉烯类抗生素作为治疗Mtb和Mab感染的潜在候选药物的潜力。
Commercial carbapenem antibiotics are being used to treat multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis. Like other β-lactams, carbapenems are irreversible inhibitors of serine d,d-transpeptidases involved in peptidoglycan biosynthesis. In addition to d,d-transpeptidases, mycobacteria also utilize nonhomologous cysteine l,d-transpeptidases (Ldts) to cross-link the stem peptides of peptidoglycan, and carbapenems form long-lived acyl-enzymes with Ldts. Commercial carbapenems are C2 modifications of a common scaffold. This study describes the synthesis of a series of atypical, C5α modifications of the carbapenem scaffold, microbiological evaluation against Mycobacterium tuberculosis (Mtb) and the nontuberculous mycobacterial species, Mycobacterium abscessus (Mab), as well as acylation of an important mycobacterial target Ldt, LdtMt2. In vitro evaluation of these C5α-modified carbapenems revealed compounds with standalone (i.e., in the absence of a β-lactamase inhibitor) minimum inhibitory concentrations (MICs) superior to meropenem-clavulanate for Mtb, and meropenem-avibactam for Mab. Time-kill kinetics assays showed better killing (2–4 log decrease) of Mtb and Mab with lower concentrations of compound 10a as compared to meropenem. Although susceptibility of clinical isolates to meropenem varied by nearly 100-fold, 10a maintained excellent activity against all Mtb and Mab strains. High resolution mass spectrometry revealed that 10a acylates LdtMt2 at a rate comparable to meropenem, but subsequently undergoes an unprecedented carbapenem fragmentation, leading to an acyl-enzyme with mass of Δm = +86 Da. Rationale for the divergence of the nonhydrolytic fragmentation of the LdtMt2 acyl-enzymes is proposed. The observed activity illustrates the potential of novel atypical carbapenems as prospective candidates for treatment of Mtb and Mab infections.
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影响因子：
5.2
作者：
Dubee, Vincent;Bernut, Audrey;Arthur, Michel
通讯作者：
Arthur, Michel
DOI：
10.1016/j.str.2012.09.016
发表时间：
2012-12-05
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Erdemli SB;Gupta R;Bishai WR;Lamichhane G;Amzel LM;Bianchet MA
通讯作者：
Bianchet MA
影响因子：
2.9
作者：
Chow, Carmen;Xu, Hua;Blanchard, John S.
通讯作者：
Blanchard, John S.
用于治疗脓肿分枝杆菌肺部疾病的抗生素的临床疗效和不良反应。
影响因子：
5.2
作者：
Chen, Jianhui;Zhao, Lan;Chu, Haiqing
通讯作者：
Chu, Haiqing
影响因子：
4.9
作者：
Cordillot, Mathilde;Dubee, Vincent;Mainardi, Jean-Luc
通讯作者：
Mainardi, Jean-Luc