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Naphthyl-Substituted Indole and Pyrrole Carboxylic Acids as Effective Antibiotic Potentiators-Inhibitors of Bacterial Cystathionine γ-Lyase.

ABSTRACT: Over the past decades, the problem of bacterial resistance to most antibiotics has become a serious threat to patients' survival. Nevertheless, antibiotics of a novel class have not been approved since the 1980s. The development of antibiotic potentiators is an appealing alternative to the challenging process of searching for new antimicrobials. Production of H₂S-one of the leading defense mechanisms crucial for bacterial survival-can be influenced by the inhibition of relevant enzymes: bacterial cystathionine γ-lyase (bCSE), bacterial cystathionine β-synthase (bCBS), or 3-mercaptopyruvate sulfurtransferase (MST). The first one makes the main contribution to H₂S generation. Herein, we present data on the synthesis, in silico analyses, and enzymatic and microbiological assays of novel bCSE inhibitors. Combined molecular docking and molecular dynamics analyses revealed a novel binding mode of these ligands to bCSE. Lead compound 2a manifested strong potentiating activity when applied in combination with some commonly used antibiotics against multidrug-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. The compound was found to have favorable in vitro absorption, distribution, metabolism, excretion, and toxicity parameters. The high effectiveness and safety of compound 2a makes it a promising candidate for enhancing the activity of antibiotics against high-priority pathogens.

SUBMITTER: Kuzovlev AS

PROVIDER: S-EPMC10671052 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Naphthyl-Substituted Indole and Pyrrole Carboxylic Acids as Effective Antibiotic Potentiators-Inhibitors of Bacterial Cystathionine γ-Lyase.

Kuzovlev Andrey S AS Zybalov Mikhail D MD Golovin Andrey V AV Gureev Maxim A MA Kasatkina Mariia A MA Biryukov Mikhail V MV Belik Albina R AR Silonov Sergey A SA Yunin Maxim A MA Zigangirova Nailya A NA Reshetnikov Vasiliy V VV Isakova Yulia E YE Porozov Yuri B YB Ivanov Roman A RA

International journal of molecular sciences 20231115 22

Over the past decades, the problem of bacterial resistance to most antibiotics has become a serious threat to patients' survival. Nevertheless, antibiotics of a novel class have not been approved since the 1980s. The development of antibiotic potentiators is an appealing alternative to the challenging process of searching for new antimicrobials. Production of H<sub>2</sub>S-one of the leading defense mechanisms crucial for bacterial survival-can be influenced by the inhibition of relevant enzyme ...[more]

PMID: 38003521

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Project description:Objective- Flow patterns differentially regulate endothelial cell phenotype, with laminar flow promoting vasodilation and disturbed flow promoting endothelial proinflammatory activation. CSE (cystathionine γ-lyase), a major source of hydrogen sulfide (H2S) in endothelial cells, critically regulates cardiovascular function, by both promoting vasodilation and reducing endothelial activation. Therefore, we sought to investigate the role of CSE in the endothelial response to flow. Approach and Results- Wild-type C57Bl/6J and CSE knockout ( CSE-/-) mice underwent partial carotid ligation to induce disturbed flow in the left carotid. In addition, endothelial cells isolated from wild-type and CSE -/- mice were exposed to either laminar or oscillatory flow, an in vitro model of disturbed flow. Interestingly, laminar flow significantly reduced CSE expression in vitro, and only disturbed flow regions show discernable CSE protein expression in vivo, correlating with enhanced H2S production in wild-type C57BL/6J but not CSE-/- mice. Lack of CSE limited disturbed flow-induced proinflammatory gene expression (ICAM-1[intercellular adhesion molecule 1], VCAM-1 [vascular cell adhesion molecular 1]) and monocyte infiltration and CSE-/- endothelial cells showed reduced NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and proinflammatory gene expression in response to oscillatory flow in vitro. In addition, CSE-/- mice showed reduced inward remodeling after partial carotid ligation. CSE-/- mice showed elevated vascular nitrite levels (measure of nitric oxide [NO]) in the unligated carotids, suggesting an elevation in baseline NO production, and the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide normalized the reduced inward remodeling, but not inflammation, of ligated carotids in CSE-/- mice. Conclusions- CSE expression in disturbed flow regions critically regulates both endothelial activation and flow-dependent vascular remodeling, in part through altered NO availability.

Project description:Traditionally, hydrogen sulfide (H2S) was simply considered as a toxic and foul smelling gas, but recently H2S been brought into the spot light of cardiovascular research and development. Since the 1990s, H2S has been mounting evidence of physiological properties such as immune modification, vascular relaxation, attenuation of oxidative stress, inflammatory mitigation, and angiogenesis. H2S has since been recognized as the third physiological gaseous signaling molecule, along with CO and NO [65,66]. H2S is produced endogenously through several key enzymes, including cystathionine β-lyase (CBE), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MST)/cysteine aminotransferase (CAT). These specific enzymes are expressed accordingly in various organ systems and CSE is the predominant H2S-producing enzyme in the cardiovascular system. The cystathionine γ-lyase (CSE)/H2S pathway has demonstrated various cardioprotective effects, including anti-atherosclerosis, anti-hypertension, pro-angiogenesis, and attenuation of myocardial ischemia-reperfusion injury. CSE exhibits its anti-atherosclerotic effect through 3 mechanisms, namely reduction of chemotactic factor inter cellular adhesion molecule-1 (ICAM-1) and CX3CR1, inhibition of macrophage lipid uptake, and induction of smooth muscle cell apoptosis via MAPK pathway. The CSE/H2S pathway's anti-hypertensive properties are demonstrated via aortic vasodilation through several mechanisms, including the direct stimulation of KATP channels of vascular smooth muscle cells (VSMCs), induction of MAPK pathway, and reduction of homocysteine buildup. Also, CSE/H2S pathway plays an important role in angiogenesis, particularly in increased endothelial cell growth and migration, and in increased vascular network length. In myocardial ischemia-reperfusion injuries, CSE/H2S pathway has shown a clear cardioprotective effect by preserving mitochondria function, increasing antioxidant production, and decreasing infarction injury size. However, CSE/H2S pathway's role in inflammation mitigation is still clouded, due to both pro and anti-inflammatory results presented in the literature, depending on the concentration and form of H2S used in specific experiment models.

Dataset Information

Naphthyl-Substituted Indole and Pyrrole Carboxylic Acids as Effective Antibiotic Potentiators-Inhibitors of Bacterial Cystathionine γ-Lyase.

Publications

Naphthyl-Substituted Indole and Pyrrole Carboxylic Acids as Effective Antibiotic Potentiators-Inhibitors of Bacterial Cystathionine γ-Lyase.

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