Opposing effects of aminocoumarins and fluoroquinolones on the SOS response and adaptability in Staphylococcus aureus

Schröder, Wiebke; Goerke, Christiane; Wolz, Christiane

doi:10.1093/jac/dks456

Cited by 54 publications

(67 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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). The small-molecule N6-(1-naphthyl)-ADP acts as an ATP competitor, which prevents the formation of the RecA-DNA filament that is essential for all RecAassociated functions (29).…”

mentioning

confidence: 99%

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

Valencia

Esposito

Spira

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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).

show abstract

mentioning

confidence: 99%

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

Valencia

Esposito

Spira

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…18 Cellular processes acting upon the ternary complexes have been hypothesized to be responsible for the double-stranded DNA breakage that occurs, along with the rapid induction of the SOS response. 19,20 It has been suggested that the rapid inhibition of DNA synthesis is specifically associated with gyrase molecules located at the replication fork. 21 Early studies of the addition of nalidixic acid to E. coli showed no inhibition of RNA synthesis for ~2 h along with continued increase in cell mass, consistent with the microscopic observation of cell filamentation.…”

Section: Discussionmentioning

confidence: 99%

Distinguishing On-Target versus Off-Target Activity in Early Antibacterial Drug Discovery Using a Macromolecular Synthesis Assay

Cunningham¹,

Kwan²,

Nelson³

et al. 2013

SLAS Discovery

View full text Add to dashboard Cite

The macromolecular synthesis assay was optimized in both S. aureus and E. coli imp and used to define patterns of inhibition of DNA, RNA, protein, and cell wall biosynthesis of several drug classes. The concentration of drug required to elicit pathway inhibition differed among the antimicrobial agents tested, with inhibition detected at concentrations significantly below the minimum inhibitory concentration (MIC) for tedizolid; within 4-fold of the MIC for ciprofloxacin, cefepime, vancomycin, tetracycline, and chloramphenicol; and significantly above the MIC for rifampicin and kanamycin. In a DNA gyrase/topoisomerase IV structure-based drug design optimization program, the assay rapidly identified undesirable off-target activity within certain chemotypes, altering the course of the program to focus on the series that maintained on-target activity.

show abstract

“…Novobiocin, the structurally related chlorobiocin as well as coumermycin A1 are 3-amino-4,7-dihydroxycoumarin derivatives, alternatively referred to as the classical aminocoumarin antibiotics. Classical aminocoumarins act as competitive inhibitors of bacterial topoisomerase, more precisely DNA gyrase [5,6]. Competitive inhibition of DNA gyrase by the classical aminocoumarin antibiotics results from an overlap in binding sites between the sugar moiety of the aminocoumarins (Figure 1, numbered in blue) and the adenine ring of ATP which is required for the gyrase activity [7].…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, differences in the binding sites between the fluoroquinolone antibiotics (e.g. moxifloxacin which primarily inhibits topoisomerase IV but also interacts with gyrase) allow fluoroquinolone antibiotics to maintain potency in aminocoumarin resistant bacteria and vice versa [5,6,11]. Mycobacterial gyrase, which is a validated drug target in Mycobacterium tuberculosis, is also the likely target for the fluoroquinolone class antibiotics as M. tuberculosis does not express the topoisomerase IV enzyme [12].…”

Section: Introductionmentioning

confidence: 99%

Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents

Kapp

Visser

Sampson

et al. 2017

Preprint

View full text Add to dashboard Cite

An in vitro medium-throughput screen using M. tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity. From this initial screen, eleven 7-substituted coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at a 50 µM concentration. This prompted further exploration of all the 7-substituted coumarins in our library, nineteen in total, as potential antimycobacterial agents. Four derivatives showed promising antimycobacterial activity with MIC99 values of 8.31 -29.70 µM and 44.15 -57.17 µM on M. tuberculosis H37Rv in independent assays using Gaste-Fe and 7H9 + OADC media, respectively. These compounds were found to bind to albumin which may explain the variations in MIC between the two assays. Preliminary antimycobacterial evaluation of moxifloxacin resistant M. tuberculosis show that these compounds are able to maintain their activity in fluoroquinolone resistant mycobacteria. Analysis of structure activity relationships for antimycobacterial versus neuronal enzyme inhibitory activity indicate that structural modification on position 4 and/or 7 of the coumarin scaffold may be utilized to improve selectivity towards either inhibition of neuronal enzymes or antimycobacterial effect. Cytotoxicity evaluations of the compounds indicate moderate cytotoxicity with slight selectivity towards mycobacteria. Further neuroprotective assays on SH-SY5Y human neuroblastoma cells indicate significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties. These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and/or neuroprotective agents.

show abstract

Opposing effects of aminocoumarins and fluoroquinolones on the SOS response and adaptability in Staphylococcus aureus

Abstract: In summary, aminocoumarins inhibit recA expression in S. aureus and probably delay the process of developing antibiotic resistance and gene transfer. A clinical re-evaluation of these compounds as well as designing more applicable derivatives should be considered.

Cited by 54 publications

References 61 publications

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

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

Distinguishing On-Target versus Off-Target Activity in Early Antibacterial Drug Discovery Using a Macromolecular Synthesis Assay

Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents

Contact Info

Product

Resources

About