Suramin is a potent and selective inhibitor of Mycobacterium tuberculosis RecA protein and the SOS response: RecA as a potential target for antibacterial drug discovery

Nautiyal, Astha; Patil, K. Neelakanteshwar; Muniyappa, K.

doi:10.1093/jac/dku080

Cited by 95 publications

(67 citation statements)

References 42 publications

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“…In the absence of c‐di‐AMP, it was found that > 95% of RecA nucleoprotein filaments exhibit an extended filamentous structure, suggesting cooperative polymerization of RecA (Fig. A); this is, consistent with the characteristic features reported for EcRecA‐ssDNA filaments by AFM visualization (Nautiyal et al, ). Under similar conditions, c‐di‐AMP causes substantial disruption and shrinkage of MtRecA‐ssDNA and MsRecA‐ssDNA filaments (Fig.…”

Section: Resultsmentioning

confidence: 99%

The second messenger cyclic di‐AMP negatively regulates the expression of Mycobacterium smegmatis recA and attenuates DNA strand exchange through binding to the C‐terminal motif of mycobacterial RecA proteins

Manikandan

Prasad

Srivastava

et al. 2018

Molecular Microbiology

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Cyclic di-GMP and cyclic di-AMP are second messengers produced by a wide variety of bacteria. They influence bacterial cell survival, biofilm formation, virulence and bacteria-host interactions. However, many of their cellular targets and biological effects are yet to be determined. A chemical proteomics approach revealed that Mycobacterium smegmatis RecA (MsRecA) possesses a high-affinity cyclic di-AMP binding activity. We further demonstrate that both cyclic di-AMP and cyclic di-GMP bind specifically to the C-terminal motif of MsRecA and Mycobacterium tuberculosis RecA (MtRecA). Escherichia coli RecA (EcRecA) was devoid of cyclic di-AMP binding but have cyclic di-GMP binding activity. Notably, cyclic di-AMP attenuates the DNA strand exchange promoted by MsRecA as well as MtRecA through the disassembly of RecA nucleoprotein filaments. However, the structure and DNA strand exchange activity of EcRecA nucleoprotein filaments remain largely unaffected. Furthermore, M. smegmatis ΔdisA cells were found to have undetectable RecA levels due to the translational repression of recA mRNA. Consequently, the ΔdisA mutant exhibited enhanced sensitivity to DNA-damaging agents. Altogether, this study points out the importance of sequence diversity among recA genes, the role(s) of cyclic di-AMP and reveals a new mode of negative regulation of recA gene expression, DNA repair and homologous recombination in mycobacteria.

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Section: Resultsmentioning

confidence: 99%

The second messenger cyclic di‐AMP negatively regulates the expression of Mycobacterium smegmatis recA and attenuates DNA strand exchange through binding to the C‐terminal motif of mycobacterial RecA proteins

Manikandan

Prasad

Srivastava

et al. 2018

Molecular Microbiology

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“…These findings have been supported genetically, as deletion of SOS response genes enhances drug susceptibility [11,16], while over-expression of mismatch repair genes confers protection [16,33]. Moreover, biochemical inhibition of RecA with polysulfonated compounds potentiates the lethality of multiple antibiotics against both Gram-negative and Gram-positive bacteria [61,62]. Oxidative damage to the nucleotide pool may, in part, underlie this phenotype [29], as incorporation of 8-oxo-guanine induces mismatch repair defects that trigger the formation of double-stranded DNA breaks [16].…”

Section: Bactericidal Processesmentioning

confidence: 99%

Antibiotic efficacy — context matters

Yang

Bening

Collins

2017

Current Opinion in Microbiology

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Antibiotic lethality is a complex physiological process, sensitive to external cues. Recent advances using systems approaches have revealed how events downstream of primary target inhibition actively participate in antibiotic death processes. In particular, altered metabolism, translational stress and DNA damage each contribute to antibiotic-induced cell death. Moreover, environmental factors such as oxygen availability, extracellular metabolites, population heterogeneity and multidrug contexts alter antibiotic efficacy by impacting bacterial metabolism and stress responses. Here we review recent studies on antibiotic efficacy and highlight insights gained on the involvement of cellular respiration, redox stress and altered metabolism in antibiotic lethality. We discuss the complexity found in natural environments and highlight knowledge gaps in antibiotic lethality that may be addressed using systems approaches.

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“…Examples of suppressors of the SOS response induced by fluoroquinolones were reported in Gram-positive and Gram-negative bacteria, such as the polyphenols baicalein (24), curcumin (25), and suramin (polysulphonated naphthylurea) (26), which have the ability to disassemble RecA single-stranded DNA filaments. Novobiocin blocks the ATP-binding site of the GyrB and inhibits ciprofloxacin and UV-induced SOS response (27,28).…”

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confidence: 99%

Ciprofloxacin-Mediated Mutagenesis Is Suppressed by Subinhibitory Concentrations of Amikacin in Pseudomonas aeruginosa

Valencia

Esposito

Spira

et al. 2017

Antimicrob Agents Chemother

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Resistance to antibiotics is a global health problem. Activation of the SOS response, and the subsequent elevation in mutagenesis, contributes to the appearance of resistance mutations. Among currently used drugs, quinolones are the most potent inducers of the SOS response. In the present study, we show that amikacin inhibits ciprofloxacin-mediated SOS induction and mutagenesis in Pseudomonas aeruginosa.KEYWORDS Pseudomonas aeruginosa, SOS response, ciprofloxacin, recA A ntibiotics may cause genetic changes involving different pathways, and one of them is the induction of error-prone polymerases mediated by SOS response (1, 2). Ciprofloxacin (CIP), one of the antimicrobials of choice for the treatment of Pseudomonas aeruginosa, induces the SOS response (3-5) by interfering with gyrase or topoisomerase activity (6, 7). The SOS regulon controls 15 genes, including imuABC and dinB (4, 5), which encode error-prone polymerases (8,9). By inducing the SOS response, ciprofloxacin increases mutagenesis (e.g., see references 10 and 11), facilitating the appearance of drug resistance.We investigated the effect of antibiotic combinations on the SOS response and mutagenesis induced by ciprofloxacin in P. aeruginosa PAO1. recA is among the SOS-regulated genes in this organism (4,5). To analyze the induction of the SOS response, we constructed a chromosomal PrecA-lux reporter. The regulatory region upstream from recA (Ϫ501 bp relative to the start codon) was cloned into the pUC18T-mini-Tn7T-lux-Gm plasmid (12) and transferred to P. aeruginosa for integration at attTn7, resulting in strain attTn7::PrecA-lux. The effect of antibiotics on the expression of the reporter was evaluated in solid medium using disk-based qualitative assays. The PrecA-lux strain was diluted to an optical density at 260 nm (OD 600 ) of 0.1. Fifty microliters of this dilution was seeded on Mueller-Hinton (MH) agar, and test antibiotic disks and CIP (5 g) disks (Sensifar-Cefar, Brazil) were placed close to one another to observe the effect of the antibiotic interaction on recA expression. Luciferase activity was detected in the ChemiDoc MP system (Bio-Rad, USA).Amikacin (AMI), imipenem, meropenem, polymyxin B, ceftazidime, cefepime, and aztreonam were tested, representing different drug classes. We found that amikacin is not an inducer of the SOS response but is in fact a strong inhibitor of recA induction by sub-MICs of ciprofloxacin (Fig. 1A). Amikacin is an aminoglycoside derived from kanamycin (13). Aminoglycosides bind, with high affinity, to the A-site on the 16S rRNA of the 30S ribosome (14) and can cause mRNA decoding errors, block mRNA and tRNA translocation, and inhibit ribosome recycling (15).

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Suramin is a potent and selective inhibitor of Mycobacterium tuberculosis RecA protein and the SOS response: RecA as a potential target for antibacterial drug discovery

Abstract: Our findings suggest a strategy to chemically disrupt the vital processes controlled by RecA and hence the promise of small molecules for use against drug-susceptible as well as drug-resistant strains of M. tuberculosis for better infection control and the development of new therapies.

Cited by 95 publications

References 42 publications

The second messenger cyclic di‐AMP negatively regulates the expression of Mycobacterium smegmatis recA and attenuates DNA strand exchange through binding to the C‐terminal motif of mycobacterial RecA proteins

The second messenger cyclic di‐AMP negatively regulates the expression of Mycobacterium smegmatis recA and attenuates DNA strand exchange through binding to the C‐terminal motif of mycobacterial RecA proteins

Antibiotic efficacy — context matters

Ciprofloxacin-Mediated Mutagenesis Is Suppressed by Subinhibitory Concentrations of Amikacin in Pseudomonas aeruginosa

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