RNA polymerase mutations cause cephalosporin resistance in clinicalNeisseria gonorrhoeaeisolates

AbstractIncreasingNeisseria gonorrhoeaeresistance to ceftriaxone, the last antibiotic recommended for empiric gonorrhea treatment, poses an urgent public health threat. However, the genetic basis of reduced susceptibility to ceftriaxone is not completely understood: while most ceftriaxone resistance in clinical isolates is caused by target site mutations inpenA, others lack these mutations. Here, we show thatpenA-independent ceftriaxone resistance has evolved multiple times through distinct mutations inrpoBandrpoD. We identify five mutations in these genes that each increase resistance to ceftriaxone, including one mutation that arose independently in two lineages, and show that clinical isolates from multiple lineages are a single nucleotide change from ceftriaxone resistance. These RNA polymerase mutations result in large-scale transcriptional changes without altering susceptibility to other antibiotics, reducing growth rate, or deranging cell morphology. These results underscore the unexpected diversity of pathways to resistance and the importance of continued surveillance for novel resistance mutations.