TY - JOUR T1 - RNA polymerase mutations cause cephalosporin resistance in clinical Neisseria gonorrhoeae isolates JF - bioRxiv DO - 10.1101/626457 SP - 626457 AU - Samantha G. Palace AU - Yi Wang AU - Daniel H. F. Rubin AU - Michael A. Welsh AU - Suzanne Walker AU - Yonatan H. Grad Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/05/03/626457.abstract N2 - The rising incidence of Neisseria gonorrhoeae infection and antimicrobial resistance imperils effective therapy for gonococcal infections 1–4. Current first-line therapy for gonorrhea relies on ceftriaxone (CRO), an extended spectrum cephalosporin (ESC), as the backbone of treatment. Dual therapy with azithromycin was intended to delay the emergence of resistance, but rising azithromycin resistance rates have been reported 2, 5, resulting in revision of United Kingdom treatment guidelines to CRO monotherapy 6. With no clear next-line agent, gonococcal resistance to ESCs is a problem of paramount clinical importance, underscored by recent reports of treatment failure and global spread of a multidrug-resistant strain 4, 7. Reduced susceptibility to ceftriaxone (CRORS) is most commonly associated with interspecies mosaic and other alleles of penA (PBP2) 8–10, the primary target of ESCs 8, 11. However, collections of clinical specimens often include isolates with high-level reduced susceptibility to ESCs (ESCRS) that is not attributable to penA variation 3, 12, 13. Here, we describe the genetic basis of reduced susceptibility in three such isolates collected in the United States. Each of these isolates has a unique mutation in the RNA polymerase holoenzyme that causes phenotypic CRORS when introduced into susceptible strains. We demonstrate that other clinical isolates can develop high-level ESCRS via a single nucleotide change in RNA polymerase. This result has important implications regarding the biology underlying cephalosporin resistance, the potential for de novo evolution of resistance under cephalosporin monotherapy, and the accuracy of sequence-based diagnostics. ER -