RT Journal Article
SR Electronic
T1 Emergence and molecular basis of azithromycin resistance in typhoidal Salmonella in Dhaka, Bangladesh
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 594531
DO 10.1101/594531
A1 Yogesh Hooda
A1 Senjuti Saha
A1 Mohammad S. I. Sajib
A1 Hafizur Rahman
A1 Stephen P. Luby
A1 Joseph Bondy-Denomy
A1 Mathuram Santosham
A1 Jason R. Andrews
A1 Samir K. Saha
YR 2019
UL http://biorxiv.org/content/early/2019/04/05/594531.abstract
AB With rising fluoroquinolone and ceftriaxone-resistant Salmonella Typhi, azithromycin, a macrolide, has become the last oral drug available against typhoid. Between 2009-2016, we isolated 1,082 Salmonella Typhi and Paratyphi A strains in Bangladesh, 13 (12 Typhi and 1 Paratyphi A) of which were azithromycin-resistant. When compared to 462 previously sequenced Typhi strains, the genomes of the 12 azithromycin-resistant Typhi strains (4.3.1 sub-clade, H58) harbored an exclusive non-synonymous single-point mutation R717Q in AcrB, an RND-efflux pump. Expression of AcrB-R717Q in E. coli and Typhi strains increased its minimum inhibitory concentration (MIC) for azithromycin by 11- and 3-fold respectively. The azithromycin-resistant Paratyphi A strain also contained a mutation at R717 (R717L), whose introduction in E. coli and Paratyphi A strains increased MIC by 7- and 3-fold respectively, confirming the role of R717 mutations in conferring azithromycin resistance. With increasing azithromycin use, strains with R717 mutations may spread leading to treatment failures, making antibiotic stewardship and vaccine introduction imperative.