Unconventional Antibacterials and Adjuvants.
Unconventional Antibacterials and Adjuvants.
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DOI：
10.1021/acs.accounts.0c00776
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发表时间：
2021-02-16
影响因子：
18.3
通讯作者：
Mobashery S
中科院分区：
文献类型：
--
作者：
Chang M;Mahasenan KV;Hermoso JA;Mobashery S
鉴于缺乏治疗细菌感染的临床选择，对新型抗菌药物的需求是真实的。20世纪40年代至70年代抗生素的巨大发现，被人们怀念地称为抗生素的黄金时代，在过去几十年里，面对耐药细菌的出现，抗生素的发现并没有跟上。人们对旧药物重新产生了兴趣，对现有抗生素的重新利用以及对协同抗生素或抗生素与佐剂的配对。尽管如此，发现这些救命药物的新类别已经变得越来越困难，需要新的范例。在此，我们描述了我们实验室使用计算和多学科实验方法发现新的抗菌剂和佐剂的三种策略。一种方法针对青霉素结合蛋白（PBPs），细胞壁肽聚糖的生物合成酶，用于发现非β-内酰胺抑制剂。在这些努力中，恶二唑和喹唑啉酮成为了两个结构类。这两类抗生素的数百种类似物已经在我们的实验室合成并充分表征。第二种方法尝试抑制细胞壁生物合成的变构调节。本文概述了在我们实验室中发现的金黄色葡萄球菌PBP2a变构调节的机制细节。该蛋白的变构位点与活性位点的距离为60 Å，因此前者的配体结合使底物能够接近后者。我们已经证明，喹唑啉类药物和头孢他林（第五代头孢菌素）都与变构位点结合，表现出抗菌活性。抑制调节磷酸化事件的尝试确定了三类抗菌佐剂和一类抗菌药物，吡啶酰胺。这些撞击的化学结构通过数百种类似物的合成而多样化。这些类似物在各种鉴定方法中具有佐剂和抗菌活性。此外，我们重新审视了bulgecins的机制，这是20世纪80年代发现并放弃的一类佐剂。这些化合物增强β-内酰胺类抗生素的活性，通过在细菌复制过程中在隔膜形成的部位形成凸起，这是包膜结构薄弱的点。这些肿块破裂，导致细菌死亡。Bulgecin A抑制铜绿假单胞菌的裂解转糖基酶Slt，可能是其细胞壁肽聚糖转换的过渡状态模拟物。一旦β-内酰胺类抗生素对细胞壁造成损伤，Slt的功能是修复损伤。当Slt被bulgecin A抑制时，生物体无法应对它，并将进行快速裂解。Bulgecin A是β-内酰胺类抗生素的有效佐剂。这些小分子类抗菌药或抗菌药佐剂的发现为治疗细菌感染的策略带来了希望。
CONSPECTUS: The need for new classes of antibacterials is genuine in light of the dearth of clinical options for the treatment of bacterial infections. The prodigious discoveries of antibiotics during the 1940s to 1970s, a period wistfully referred to as the Golden Age of Antibiotics, have not kept up in the face of emergence of resistant bacteria in the past few decades. There has been a renewed interest in old drugs, the repurposing of the existing antibiotics and pairing of synergistic antibiotics or of an antibiotic with an adjuvant. Notwithstanding, discoveries of novel classes of these life-saving drugs have become increasingly difficult, calling for new paradigms. We describe, herein, three strategies from our laboratories toward discoveries of new antibacterials and adjuvants using computational and multidisciplinary experimental methods. One approach targets penicillin-binding proteins (PBPs), biosynthetic enzymes of cell-wall peptidoglycan, for discoveries of non-β-lactam inhibitors. Oxadiazoles and quinazolinones emerged as two structural classes out of these efforts. Several hundred analogs of these two classes of antibiotics have been synthesized and fully characterized in our laboratories. A second approach ventures into inhibition of allosteric regulation of cell-wall biosynthesis. The mechanistic details of allosteric regulation of PBP2a of Staphylococcus aureus, discovered in our laboratories, is outlined. The allosteric site in this protein is at 60 Å distance to the active site, whereby ligand binding at the former makes access to the latter by the substrate possible. We have documented that both quinazolinones and ceftaroline, a fifth-generation cephalosporin, bind to the allosteric site in manifestation of the antibacterial activity. Attempts at inhibition of the regulatory phosphorylation events identified three classes of antibacterial adjuvants and one class of antibacterials, the picolinamides. The chemical structures for these hits went through diversification by synthesis of hundreds of analogs. These analogs were characterized in various assays for identification of leads with adjuvant and antibacterial activities. Furthermore, we revisited the mechanism of bulgecins, a class of adjuvants discovered and abandoned in the 1980s. These compounds potentiate the activities of β-lactam antibiotics by the formation of bulges at the sites of septum formation during bacterial replication, which are points of structural weakness in the envelope. These bulges experience rupture, which leads to bacterial death. Bulgecin A inhibits the lytic transglycosylase Slt of Pseudomonas aeruginosa as a likely transition-state mimetic for its turnover of the cell-wall peptidoglycan. Once damage to cell wall is inflicted by a β-lactam antibiotic, the function of Slt is to repair the damage. When Slt is inhibited by bulgecin A, the organism cannot cope with it and would undergo rapid lysis. Bulgecin A is an effective adjuvant of β-lactam antibiotics. These discoveries of small-molecule classes of antibacterials or of adjuvants to antibacterials hold promise in strategies for treatment of bacterial infections.
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影响因子：
3.3
作者：
El-Gendy, Mervat M. A.;Shaaban, Mohamed;Laatsch, Hartmut
通讯作者：
Laatsch, Hartmut
影响因子：
4.6
作者：
Byun B;Mahasenan KV;Dik DA;Marous DR;Speri E;Kumarasiri M;Fisher JF;Hermoso JA;Mobashery S
通讯作者：
Mobashery S
变构反应的破坏是对抗生素抗药性的前所未有的机制。
影响因子：
15
作者：
Fishovitz, Jennifer;Rojas-Altuve, Alzoray;Otero, Lisandro H.;Dawley, Matthew;Carrasco-Lopez, Cesar;Chang, Mayland;Hermoso, Juan A.;Mobashery, Shahriar
通讯作者：
Mobashery, Shahriar
影响因子：
15
作者：
Fuda, C;Hesek, D;Mobashery, S
通讯作者：
Mobashery, S
影响因子：
4.8
作者：
Fuda, C;Suvorov, M;Mobashery, S
通讯作者：
Mobashery, S