Structural insights into the inhibition of bacterial RecA by naphthalene polysulfonated compounds

Zhou, Ziyuan; Pan, Qing; Lv, Xinchen; Yuan, Jing; Zhang, Yang; Zhang, Mingxia; Ke, Ming; Mo, Xiao-Mei; Xie, Yun; Liu, Yingxia; Chen, Ting; Liang, Mingchan; Yin, Feng; Liu, Lei; Zhou, Yiqing; Qiao, Kun; Li, Rui; Li, Zigang; Wong, Nai-Kei

doi:10.1016/j.isci.2020.101952

Cited by 9 publications

(6 citation statements)

References 66 publications

(61 reference statements)

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“…Consequently, attenuation of the SOS response system via preferential inhibition of RecA has been proposed as a possible therapeutic target to block the development of multi-drug resistance and resistance-conferring mutagenesis (Mo et al ., 2016, Thi et al ., 2011). Several inhibitors of RecA activities in vitro have been developed including ATP-competitive nucleotide analogs (Lee et al ., 2005,Wigle et al ., 2006), polysulfated naphthyl compounds (Wigle and Singleton, 2007, Nautiyal et al ., 2014, Zhou et al ., 2021), as well as short peptides (Yakimov et al ., 2017). To our knowledge, none of these synthetic small molecules have demonstrated RecA-specific biological activities in bacterial cell cultures.…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

Cyclic di-AMP regulates genome stability and drug resistance in Mycobacterium through RecA-dependent and -independent recombination

Mudgal,

Goyal,

Manikandan

et al. 2024

Preprint

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InEscherichia coli, RecA plays a central role in the rescue of stalled replication forks, double-strand break (DSB) repair, homologous recombination (HR) and induction of the SOS response. While the RecA-dependent pathway is dominant, alternative HR pathways that function independently of RecA do exist, but relatively little is known about the underlying mechanism. Several studies have documented that a variety of proteins act either as positive or negative regulators of RecA to ensure high-fidelity HR and genomic stability. Along these lines, we previously demonstrated that the second messenger cyclic di-AMP binds to mycobacterial RecA proteins, but notE. coliRecA, and inhibits its DNA strand exchange activity in vitro via the disassembly of RecA nucleoprotein filaments. Herein, we demonstrate thatMycobacterium smegmatis ΔdisAcells, which lack c-di-AMP, exhibit increased DNA recombination, higher frequency of mutation and gene duplications during RecA-dependent and RecA-independent DSB repair. We also found that c-di-AMP regulates SOS response by inhibiting RecA-mediated self-cleavage of LexA repressor and its absence enhances drug resistance inM. smegmatis ΔdisAcells. Together, our results uncover a role of c-di-AMP in the maintenance of genomic stability through modulation of DSB repair inM. smegmatis.

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Section: Discussion and Perspectivesmentioning

confidence: 99%

Cyclic di-AMP regulates genome stability and drug resistance in Mycobacterium through RecA-dependent and -independent recombination

Mudgal,

Goyal,

Manikandan

et al. 2024

Preprint

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“…Different studies have been performed to develop inhibitor against the RecA of Gram's negative bacteria, including suramin for M. tuberculosis (Nautiyal et al, 2014), naphthalene polysulfonated compounds (Zhou et al, 2021), N6-(1-naphthyl)-ADP against RecA (Lee et al, 2005), designed helix against RecA (Cline et al, 2007), Phthalocyanine tetrasulfonic acid (Alam et al, 2016), the alpha-helical peptide of RecX protein against RecA of E. coli (Yakimov et al, 2017). We have previously reported an in-silico screened lead ZINC01530654 against the RecA protein of A. baumannii .…”

Section: Discussionmentioning

confidence: 99%

“…Hence, an inhibitor of the RecA protein of A. baumannii can enhance the efficacy of current therapies. There are different studies reported inhibitors targeting bacterial RecA protein such as suramin for Mycobacterium tuberculosis (Nautiyal et al, 2014), and naphthalene polysulfonated compounds (Zhou et al, 2021), N6-(1-naphthyl)-ADP (Lee et al, 2005), designed helix (Cline et al, 2007), Phthalocyanine tetrasulfonic acid (Alam et al, 2016), alpha-helical peptide of RecX protein against the RecA of Escherichia coli (Yakimov et al, 2017). Recently, curcumin-thalidomide hybrids show high predicted binding to RecA compared to the curcumin analogs in E. coli and M. tuberculosis (Zhou et al, 2019) suggesting hybrid molecules may be promising to target RecA protein.…”

Section: Introductionmentioning

confidence: 99%

Pharmacophore screening, denovo designing, retrosynthetic analysis, and combinatorial synthesis of a novel lead VTRA1.1 against RecA protein of Acinetobacter baumannii

Tiwari

2022

Chem Biol Drug Des

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Antibiotics and disinfectants resistance is acquired by activating RecA-mediated DNA repair, which maintains ROS-dependent DNA damage caused by the antimicrobial molecules. To increase the efficacy of different antimicrobials, an inhibitor can be developed against RecA protein. The present study aims to design a denovo inhibitor against RecA protein of Acinetobacter baumannii.Pharmacophore-based screening, molecular mechanics, molecular dynamics simulation (MDS), retrosynthetic analysis, and combinatorial synthesis were used to design lead VTRA1.1 against RecA of A. baumannii. Pharmacophore models (structure-based and ligand-based) were created, and a phase library of FDA-approved drugs was prepared. Screening of the phase library against these pharmacophore models selected thirteen lead molecules. These filtered leads were used for the denovo fragment-based design, which produced 253 combinations. These designed molecules were further analyzed for its interaction with active site of RecA that selected a hybrid VTRA1. Further, retrosynthetic analysis and combinatorial synthesis produced 1000 analogs of VTRA1 by more than 100 modifications. These analogs were used for XP docking, binding free energy calculation, and MDS analysis which finally select lead VTRA1.1 against RecA protein. Further, mutations at the interacting residues of RecA with VTRA1.1, alter the unfolding rate of RecA, which suggests the binding of VTRA1.1 to these residues may alter the stability of RecA. It is also found that VTRA1.1 had reduced interaction of RecA with LexA and ssDNA polydT, showing the lead's efficacy in controlling the SOS response. Further, it was also observed that VTRA1.1 does not contain any predicted human off-targets and no cytotoxicity to cell lines.As functional RecA is involved in antimicrobial resistance, denovo designed lead VTRA1.1 against RecA may be further developed as a significant combination for therapeutic uses against A. baumannii.

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“… 47 There are reports on RecA inhibitors that are currently being developed for clinical applications. 54 The SOS response was initially recognized as regulating DNA damage repair. However, it has been observed to play a much broader role.…”

Section: Way Forward: Emerging Strategies For Tackling Antibiotic Res...mentioning

confidence: 99%

“…Inhibitors of the SOS response can not only prevent the development of antibiotic resistance, particularly, when the drug is present in sub‐lethal concentrations, but they can also enhance the activities of bactericidal antibiotics 47 . There are reports on RecA inhibitors that are currently being developed for clinical applications 54 . The SOS response was initially recognized as regulating DNA damage repair.…”

Section: Way Forward: Emerging Strategies For Tackling Antibiotic Res...mentioning

confidence: 99%

Antibiotic resistance: The challenges and some emerging strategies for tackling a global menace

Nwobodo

Ugwu

Anie

et al. 2022

Clinical Laboratory Analysis

270

104

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Background Antibiotic resistance is currently the most serious global threat to the effective treatment of bacterial infections. Antibiotic resistance has been established to adversely affect both clinical and therapeutic outcomes, with consequences ranging from treatment failures and the need for expensive and safer alternative drugs to the cost of higher rates of morbidity and mortality, longer hospitalization, and high‐healthcare costs. The search for new antibiotics and other antimicrobials continues to be a pressing need in humanity's battle against bacterial infections. Antibiotic resistance appears inevitable, and there is a continuous lack of interest in investing in new antibiotic research by pharmaceutical industries. This review summarized some new strategies for tackling antibiotic resistance in bacteria. Methods To provide an overview of the recent research, we look at some new strategies for preventing resistance and/or reviving bacteria's susceptibility to already existing antibiotics. Results Substantial pieces of evidence suggest that antimicrobials interact with host immunity, leading to potent indirect effects that improve antibacterial activities and may result in more swift and complete bactericidal effects. A new class of antibiotics referred to as immuno‐antibiotics and the targeting of some biochemical resistance pathway components including inhibition of SOS response and hydrogen sulfide as biochemical underlying networks of bacteria can be considered as new emerging strategies to combat antibiotic resistance in bacteria. Conclusion This review highlighted and discussed immuno‐antibiotics and inhibition of SOS response and hydrogen sulfide as biochemical underlying networks of bacteria as new weapons against antibiotic resistance in bacteria.

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Structural insights into the inhibition of bacterial RecA by naphthalene polysulfonated compounds

Cited by 9 publications

References 66 publications

Cyclic di-AMP regulates genome stability and drug resistance in Mycobacterium through RecA-dependent and -independent recombination

Cyclic di-AMP regulates genome stability and drug resistance in Mycobacterium through RecA-dependent and -independent recombination

Pharmacophore screening, denovo designing, retrosynthetic analysis, and combinatorial synthesis of a novel lead VTRA1.1 against RecA protein of Acinetobacter baumannii

Antibiotic resistance: The challenges and some emerging strategies for tackling a global menace

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