Anastasia Golovina*, Eleonora Proia, Francesco Fiorentino, Maxim Yunin, Maria Kasatkina, Nailya Zigangirova, Anna Soloveva, Elena Sysolyatina, Svetlana Ermolaeva, Roman Novikov, Sergei Silonov, Sergei Pushkin, Milan Mladenović, Julia Isakova, Albina Belik, Maxim Nawrozkij, Dante Rotili, Rino Ragno* and Roman Ivanov,
{"title":"(异芳基甲基)苯甲酸作为一类新型细菌胱硫醚 γ-赖氨酸酶抑制剂:合成、生物学评价和分子建模。","authors":"Anastasia Golovina*, Eleonora Proia, Francesco Fiorentino, Maxim Yunin, Maria Kasatkina, Nailya Zigangirova, Anna Soloveva, Elena Sysolyatina, Svetlana Ermolaeva, Roman Novikov, Sergei Silonov, Sergei Pushkin, Milan Mladenović, Julia Isakova, Albina Belik, Maxim Nawrozkij, Dante Rotili, Rino Ragno* and Roman Ivanov, ","doi":"10.1021/acsinfecdis.4c00136","DOIUrl":null,"url":null,"abstract":"<p >Antibiotic resistance is one of the most serious global health threats. Therefore, there is a need to develop antimicrobial agents with new mechanisms of action. Targeting of bacterial cystathionine γ-lyase (bCSE), an enzyme essential for bacterial survival, is a promising approach to overcome antibiotic resistance. Here, we described a series of (heteroarylmethyl)benzoic acid derivatives and evaluated their ability to inhibit bCSE or its human ortholog hCSE using known bCSE inhibitor NL2 as a lead compound. Derivatives bearing the 6-bromoindole group proved to be the most active, with IC<sub>50</sub> values in the midmicromolar range, and highly selective for bCSE over hCSE. Furthermore, none of these compounds showed significant toxicity to HEK293T cells. The obtained data were rationalized by ligand-based and structure-based molecular modeling analyses. The most active compounds were also found to be an effective adjunct to several widely used antibacterial agents against clinically relevant antibiotic-resistant strains of such bacteria as <i>Staphylococcus aureus</i>, <i>Klebsiella pneumoniae</i>, and <i>Pseudomonas aeruginosa</i>. The most potent compounds, <b>3h</b> and <b>3i,</b> also showed a promising <i>in vitro</i> absorption, distribution, metabolism, and excretion (ADME) profile. Finally, compound <b>3i</b> manifested potentiating activity in pneumonia, sepsis, and infected-wound <i>in vivo</i> models.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"(Heteroarylmethyl)benzoic Acids as a New Class of Bacterial Cystathionine γ-Lyase Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling\",\"authors\":\"Anastasia Golovina*, Eleonora Proia, Francesco Fiorentino, Maxim Yunin, Maria Kasatkina, Nailya Zigangirova, Anna Soloveva, Elena Sysolyatina, Svetlana Ermolaeva, Roman Novikov, Sergei Silonov, Sergei Pushkin, Milan Mladenović, Julia Isakova, Albina Belik, Maxim Nawrozkij, Dante Rotili, Rino Ragno* and Roman Ivanov, \",\"doi\":\"10.1021/acsinfecdis.4c00136\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Antibiotic resistance is one of the most serious global health threats. 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(Heteroarylmethyl)benzoic Acids as a New Class of Bacterial Cystathionine γ-Lyase Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling
Antibiotic resistance is one of the most serious global health threats. Therefore, there is a need to develop antimicrobial agents with new mechanisms of action. Targeting of bacterial cystathionine γ-lyase (bCSE), an enzyme essential for bacterial survival, is a promising approach to overcome antibiotic resistance. Here, we described a series of (heteroarylmethyl)benzoic acid derivatives and evaluated their ability to inhibit bCSE or its human ortholog hCSE using known bCSE inhibitor NL2 as a lead compound. Derivatives bearing the 6-bromoindole group proved to be the most active, with IC50 values in the midmicromolar range, and highly selective for bCSE over hCSE. Furthermore, none of these compounds showed significant toxicity to HEK293T cells. The obtained data were rationalized by ligand-based and structure-based molecular modeling analyses. The most active compounds were also found to be an effective adjunct to several widely used antibacterial agents against clinically relevant antibiotic-resistant strains of such bacteria as Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The most potent compounds, 3h and 3i, also showed a promising in vitro absorption, distribution, metabolism, and excretion (ADME) profile. Finally, compound 3i manifested potentiating activity in pneumonia, sepsis, and infected-wound in vivo models.
期刊介绍:
ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to:
* Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials.
* Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets.
* Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance.
* Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents.
* Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota.
* Small molecule vaccine adjuvants for infectious disease.
* Viral and bacterial biochemistry and molecular biology.