QnrVC reducing fluoroquinolone susceptibility in epidemic strains of Vibrio cholerae (735.6)

Abstract

Treatment of cholera still is a global challenge for health authorities across the world. It is important to use effective antimicrobials for curbing cholera and shortens the duration of illness. As per the WHO recommendations, ciprofloxacin and doxycycline are drugs of choice to be used in treatment of severe cholera. Single doses of ciprofloxacin have been reported to be better than single dose of doxycycline in eradication of cholera bacterium from stool. Earlier we have reported that reduced susceptibility or resistance to fluoroquinolones in Vibrio cholerae O1 is associated with either delay or failure in cholera treatment. V. cholerae harbours two related type II topoisomerases, which alter DNA topology through a DNA cleavage complex. Fluoroquinolones stabilizing the DNA breakage‐reunion complex inhibit DNA replication. Point mutations in gyraseA and ParC responsible for reduced susceptibility to fluoroquinolones are well known. Here, we discuss the QnrVC mediated acquired mechanism of resistance in epidemic strains of V. cholerae. PCR analyses and DNA sequencing revealed presence of qnrVC gene (encoding QnrVC) in epidemic V. cholerae O1 in strains from central and Eastern parts of India. Higher order structural analyses confirmed that QnrVC exhibits right‐handed quadrilateral beta‐helical fold. The shape, size, and charge distribution on QnrVC is reminiscent of a 30‐bp long B‐form DNA. Docking studies revealed that it occupies the entire length of the G segment DNA binding site of type II topoisomerases, thus interfering with fluoroqunolone action. Strains harbouring the qnrVC elements were either resistant or less susceptible to ciprofloxacin as per CLSI, 2010 USA guidelines. Cloning of qnrVC in E. coli transformant mediated 4‐8 folds increment of MIC for ciprofloxacin. The use fluoroquinolones in cholera cases should be closely monitored and development of alternate chemotherapeutic agents targetting transition type II topoisomerases should be given due priority. Grant Funding Source: UGC, DBT and DST, Govt. of India