Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis.
Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis.
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DOI：
10.1002/chem.202200995
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发表时间：
2022-09-12
影响因子：
4.3
通讯作者：
Aldrich, Courtney C.
中科院分区：
文献类型：
--
作者：
Cole, Malcolm S.;Howe, Michael D.;Buonomo, Joseph A.;Sharma, Sachin;Lamont, Elise A.;Brody, Scott, I;Mishra, Neeraj K.;Minato, Yusuke;Thiede, Joshua M.;Baughn, Anthony D.;Aldrich, Courtney C.
结核病（TB）是全球传染病死亡的主要来源。据估计，抗生素耐药菌株占结核病新发病例的10%，因此迫切需要新的治疗方法。传统上，β -内酰胺类抗生素对结核分枝杆菌（Mtb）无效，这是由于生物体固有的β -内酰胺酶表达会破坏亲电的β -内酰胺战斗部。我们开发了新的β -内酰胺缀合物，利用这种固有的β -内酰胺酶活性来实现吡嗪酸（POA）的选择性释放，吡嗪酸是一线结核病药物的活性形式。这些偶联物对结核分枝杆菌和相关分枝杆菌具有选择性活性，并且在多种耐药菌株和模型中活性保持甚至增强。初步的机制研究表明，POA“弹头”和β -内酰胺“促进子”都有助于观察到的活性，这表明了一种对未来结核病治疗具有重要意义的联合药物策略。头孢-吡嗪酸（POA）偶联物被合成为耐药结核病（TB）的新药物。我们的策略规避了pncA相关的耐药突变，这些突变威胁到一线抗结核吡嗪酰胺（PZA）的持续使用，并且还显示出对其他耐药菌株和模型的有希望的活性，通过双重治疗方式的联合作用实现了共药效应。
Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic‐resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β‐lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β‐lactamases that destroy the electrophilic β‐lactam warhead. We have developed novel β‐lactam conjugates, which exploit this inherent β‐lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first‐line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA “warhead” as well as the β‐lactam “promoiety” contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy. Cephem‐pyrazinoic acid (POA) conjugates were synthesized as novel agents for drug‐resistant Tuberculosis (TB). Our strategy circumvents pncA‐linked resistance mutations, which threaten continued use of the first‐line antitubercular pyrazinamide (PZA), and also demonstrates promising activity against other resistant strains and models, achieving a codrug affect through combined action of the dual therapeutic modalities.
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影响因子：
4.9
作者：
Lanoix, Jean-Philippe;Tasneen, Rokeya;Nuermberger, Eric
通讯作者：
Nuermberger, Eric
影响因子：
11.1
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Cohen KA;El-Hay T;Wyres KL;Weissbrod O;Munsamy V;Yanover C;Aharonov R;Shaham O;Conway TC;Goldschmidt Y;Bishai WR;Pym AS
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Pym AS
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Dick T
影响因子：
7.3
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Aube, Jeffrey
影响因子：
7.3
作者：
CORRAZ, AJ;DAX, SL;WEI, CC
通讯作者：
WEI, CC