Interaction of the plasmid-encoded quinolone resistance protein QnrB19 with Salmonella Typhimurium DNA gyrase

Biological Effects of Quinolones: A Family of Broad-Spectrum Antimicrobial Agents

“…After more than two decades of the discovery of plasmid-mediated resistance to quinolones (PMQR), the genes of resistance to quinolones that can be mobilized have been described mainly in Gram-negative bacteria of clinical importance, such as E. coli , P . vulgaris , Shigella , Salmonella , K. pneumoniae , Enterobacter , A. baumannii , and P. aeruginosa [ 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 ]. To date, three resistance mechanisms have been identified in transferable elements [ 77 , 219 ].…”

“…The first mechanism is mediated by Qnr proteins that protect gyrase or topoisomerase IV from inhibition by quinolones. These proteins are encoded by the qnr genes of several families with multiple alleles, including the qnrA , qnrB , qnrC , qnrD , qnrE , qnrS , and qnrVC genes [ 77 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 220 ]. Qnr proteins are members of the PRP family (from pentapeptide repeat protein) that contain domains composed of repeating pentapeptides sequences of approximately 200 amino acids and it has been proposed that they act as DNA mimetics competing with DNA for its binding to type IV gyrase or topoisomerase [ 221 ].…”

“…Recently, it has been shown that the presence of nalidixic acid, norfloxacin or ciprofloxacin QnrB19 from Salmonella was able to restore supercoiling activity, in a concentration-dependent manner, reaching a maximum protective activity and then inhibiting supercoiling. A possible explanation would be related to its mechanism of action by competing with the DNA gyrase substrate, such as relaxed or positively supercoiled DNA, due to its structure that somehow may mimic double-stranded DNA [ 216 ]. It was also shown that QnrB19 increased the IC50 of ciprofloxacin and norfloxacin but not nalidixic acid, suggesting that these differences are related to structural differences that would affect the potency of quinolones in the presence of QnrB19 [ 216 ].…”

“…A possible explanation would be related to its mechanism of action by competing with the DNA gyrase substrate, such as relaxed or positively supercoiled DNA, due to its structure that somehow may mimic double-stranded DNA [ 216 ]. It was also shown that QnrB19 increased the IC50 of ciprofloxacin and norfloxacin but not nalidixic acid, suggesting that these differences are related to structural differences that would affect the potency of quinolones in the presence of QnrB19 [ 216 ]. QnrB19 is the predominant allele in Salmonella (>80%) and has been found in plasmid Ppab19-4, transduction has been proposed as a possible transfer mechanism, for propagation of the plasmid [ 223 ].…”

“…The second mechanism confers resistance by enzymatic modification of a variant of an aminoglycoside transferase that acetylates the unsubstituted nitrogen of the piperazine ring that has ciprofloxacin and norfloxacin in its structure, thus reducing the activity of these antimicrobials, as well as, that of some aminoglycosides and is encoded by the aac(6′)-Ib-cr gene [ 77 , 226 ]. It is a narrow spectrum mechanism inactivating only two FQs, however, it is widely distributed in Enterobacteriaceae [ 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 ]. Recently, in P. aeruginosa an ATP-phosphotransferase encoded by the crpP gene that inactivates ciprofloxacin has been described, finding homologous genes in clinical strains of extended-spectrum β-lactamase (ESBL)-producing enterobacteria, suggesting that this new gene may be highly distributed in Enterobacteriaceae [ 227 ].…”