N-Aryl mercaptoacetamides as potential multi-target inhibitors of metallo-β-lactamases (MBLs) and the virulence factor LasB from Pseudomonas aeruginosa,RSC Medicinal Chemistry

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N-Aryl mercaptoacetamides as potential multi-target inhibitors of metallo-β-lactamases (MBLs) and the virulence factor LasB from Pseudomonas aeruginosa
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-07-29 , DOI: 10.1039/d1md00187f
Samir Yahiaoui ₁ , Katrin Voos ₂ , Jörg Haupenthal ₁ , Thomas A Wichelhaus ₃ , Denia Frank ₃ , Lilia Weizel ₄ , Marco Rotter ₄ , Steffen Brunst ₄ , Jan S Kramer ₄ , Ewgenij Proschak ₄ , Christian Ducho ₂ , Anna K H Hirsch _{1,

5}

Affiliation

Increasing antimicrobial resistance is evolving to be one of the major threats to public health. To reduce the selection pressure and thus to avoid a fast development of resistance, novel approaches aim to target bacterial virulence instead of growth. Another strategy is to restore the activity of antibiotics already in clinical use. This can be achieved by the inhibition of resistance factors such as metallo-β-lactamases (MBLs). Since MBLs can cleave almost all β-lactam antibiotics, including the “last resort” carbapenems, their inhibition is of utmost importance. Here, we report on the synthesis and in vitro evaluation of N-aryl mercaptoacetamides as inhibitors of both clinically relevant MBLs and the virulence factor LasB from Pseudomonas aeruginosa. All tested N-aryl mercaptoacetamides showed low micromolar to submicromolar activities on the tested enzymes IMP-7, NDM-1 and VIM-1. The two most promising compounds were further examined in NDM-1 expressing Klebsiella pneumoniae isolates, where they restored the full activity of imipenem. Together with their LasB-inhibitory activity in the micromolar range, this class of compounds can now serve as a starting point for a multi-target inhibitor approach against both bacterial resistance and virulence, which is unprecedented in antibacterial drug discovery.

中文翻译：

N-芳基巯基乙酰胺作为金属β-内酰胺酶（MBL）和铜绿假单胞菌毒力因子LasB的潜在多靶点抑制剂

日益增加的抗微生物药物耐药性正在演变为对公共卫生的主要威胁之一。为了降低选择压力，从而避免抗性的快速发展，新方法旨在针对细菌毒力而不是生长。另一种策略是恢复已用于临床的抗生素的活性。这可以通过抑制金属-β-内酰胺酶 (MBL) 等抗性因素来实现。由于 MBL 可以裂解几乎所有 β-内酰胺类抗生素，包括“最后的手段”碳青霉烯类，它们的抑制作用至关重要。在这里，我们报告了N-芳基巯基乙酰胺作为临床相关 MBL 和来自铜绿假单胞菌的毒力因子 LasB 的抑制剂的合成和体外评估. 所有测试的N-芳基巯基乙酰胺对测试的酶 IMP-7、NDM-1 和 VIM-1 都显示出低微摩尔至亚微摩尔的活性。在表达 NDM-1 的肺炎克雷伯菌分离株中进一步检查了两种最有希望的化合物，在那里它们恢复了亚胺培南的全部活性。连同它们在微摩尔范围内的 LasB 抑制活性，这类化合物现在可以作为针对细菌耐药性和毒力的多靶点抑制剂方法的起点，这在抗菌药物发现中是前所未有的。

更新日期：2021-08-23

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