Antimicrobial activity of compounds identified by artificial intelligence discovery engine targeting enzymes involved in Neisseria gonorrhoeae peptidoglycan metabolism.

IF 4.3 2区 生物学 Q1 BIOLOGY
Ravi Kant, Hannah Tilford, Camila S Freitas, Dayana A Santos Ferreira, James Ng, Gwennan Rucinski, Joshua Watkins, Ryan Pemberton, Tigran M Abramyan, Stephanie C Contreras, Alejandra Vera, Myron Christodoulides
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引用次数: 0

Abstract

Background: Neisseria gonorrhoeae (Ng) causes the sexually transmitted disease gonorrhoea. There are no vaccines and infections are treated principally with antibiotics. However, gonococci rapidly develop resistance to every antibiotic class used and there is a need for developing new antimicrobial treatments. In this study we focused on two gonococcal enzymes as potential antimicrobial targets, namely the serine protease L,D-carboxypeptidase LdcA (NgO1274/NEIS1546) and the lytic transglycosylase LtgD (NgO0626/NEIS1212). To identify compounds that could interact with these enzymes as potential antimicrobials, we used the AtomNet virtual high-throughput screening technology. We then did a computational modelling study to examine the interactions of the most bioactive compounds with their target enzymes. The identified compounds were tested against gonococci to determine minimum inhibitory and bactericidal concentrations (MIC/MBC), specificity, and compound toxicity in vitro.

Results: AtomNet identified 74 compounds that could potentially interact with Ng-LdcA and 84 compounds that could potentially interact with Ng-LtgD. Through MIC and MBC assays, we selected the three best performing compounds for both enzymes. Compound 16 was the most active against Ng-LdcA, with a MIC50 value < 1.56 µM and MBC50/90 values between 0.195 and 0.39 µM. In general, the Ng-LdcA compounds showed higher activity than the compounds directed against Ng-LtgD, of which compound 45 had MIC50 values of 1.56-3.125 µM and MBC50/90 values between 3.125 and 6.25 µM. The compounds were specific for gonococci and did not kill other bacteria. They were also non-toxic for human conjunctival epithelial cells as judged by a resazurin assay. To support our biological data, in-depth computational modelling study detailed the interactions of the compounds with their target enzymes. Protein models were generated in silico and validated, the active binding sites and amino acids involved elucidated, and the interactions of the compounds interacting with the enzymes visualised through molecular docking and Molecular Dynamics Simulations for 50 ns and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA).

Conclusions: We have identified bioactive compounds that appear to target the N. gonorrhoeae LdcA and LtgD enzymes. By using a reductionist approach involving biological and computational data, we propose that compound Ng-LdcA-16 and Ng-LtgD-45 are promising anti-gonococcal compounds for further development.

人工智能发现引擎针对参与淋病奈瑟菌肽聚糖代谢的酶鉴定出的化合物的抗菌活性。
背景:淋病奈瑟菌(Ng)会导致性传播疾病淋病。目前还没有疫苗,主要使用抗生素治疗感染。然而,淋球菌会迅速对所有抗生素产生抗药性,因此需要开发新的抗菌治疗方法。在这项研究中,我们将淋球菌的两种酶作为潜在的抗菌目标,即丝氨酸蛋白酶 L,D-羧肽酶 LdcA(NgO1274/NEIS1546)和裂解转糖基酶 LtgD(NgO0626/NEIS1212)。为了找出能与这些酶相互作用的化合物作为潜在的抗菌剂,我们使用了 AtomNet 虚拟高通量筛选技术。然后,我们进行了计算建模研究,以检验最具生物活性的化合物与其目标酶之间的相互作用。我们对鉴定出的化合物进行了淋球菌测试,以确定最小抑菌和杀菌浓度(MIC/MBC)、特异性以及化合物的体外毒性:结果:AtomNet发现了74种可能与Ng-LdcA相互作用的化合物和84种可能与Ng-LtgD相互作用的化合物。通过 MIC 和 MBC 检测,我们选出了对这两种酶活性最好的三种化合物。化合物 16 对 Ng-LdcA 的活性最强,其 MIC50 值为结论:我们发现了似乎能靶向淋球菌 LdcA 和 LtgD 酶的生物活性化合物。通过使用涉及生物和计算数据的还原法,我们认为化合物 Ng-LdcA-16 和 Ng-LtgD-45 是有希望进一步开发的抗淋球菌化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biological Research
Biological Research 生物-生物学
CiteScore
10.10
自引率
0.00%
发文量
33
审稿时长
>12 weeks
期刊介绍: Biological Research is an open access, peer-reviewed journal that encompasses diverse fields of experimental biology, such as biochemistry, bioinformatics, biotechnology, cell biology, cancer, chemical biology, developmental biology, evolutionary biology, genetics, genomics, immunology, marine biology, microbiology, molecular biology, neuroscience, plant biology, physiology, stem cell research, structural biology and systems biology.
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