Mosaic interspecifically acquired alleles of the multiple transferable resistance (mtr) efflux pump operon correlate with increased resistance to azithromycin in Neisseria gonorrhoeae in epidemiological studies. However, whether and how these alleles cause resistance is unclear. Here, we use population genomics, transformations, and transcriptional analyses to dissect the relationship between variant mtr alleles and azithromycin resistance. We find that the locus encompassing the mtrR transcriptional repressor and the mtrCDE pump is a hot spot of interspecific recombination introducing alleles from Neisseria meningitidis and Neisseria lactamica into N. gonorrhoeae, with multiple rare haplotypes in linkage disequilibrium at mtrD and the mtr promoter region. Transformations demonstrate that resistance to azithromycin, as well as to other antimicrobial compounds such as polymyxin B and crystal violet, is mediated through epistasis between these two loci and that the full-length mosaic mtrD allele is required. Gene expression profiling reveals the mechanism of resistance in mosaics couples novel mtrD alleles with promoter mutations that increase expression of the pump. Overall, our results demonstrate that epistatic interactions at mtr gained from multiple neisserial species has contributed to increased gonococcal resistance to diverse antimicrobial agents.
18Mosaic interspecifically acquired alleles of the multiple transferable resistance (mtr) 19 efflux pump operon correlate with reduced susceptibility to azithromycin in Neisseria 20 gonorrhoeae in epidemiological studies. However, whether and how these alleles cause resistance 21 is unclear. Here, we use population genomics, transformations, and transcriptional analyses to 22 dissect the relationship between variant mtr alleles and azithromycin resistance. We find that the 23 locus encompassing the mtrR transcriptional repressor and the mtrCDE pump is a hotspot of 24 interspecific recombination introducing alleles from N. meningitidis and N. lactamica into N. 25 gonorrhoeae, with multiple rare haplotypes in linkage disequilibrium at mtrD and the mtr 26 promoter region. Transformations demonstrated that resistance is mediated through epistasis 27 between these two loci and that the full length of the mosaic mtrD allele is required. Gene 28 expression profiling revealed the mechanism of resistance in mosaics couples the novel mtrD 29 alleles with promoter mutations enhancing expression of the pump. Overall, our results 30 demonstrate that epistatic interactions at mtr gained from multiple Neisseria has contributed to 31 azithromycin resistance in the gonococcal population. 32
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AUTHOR SUMMARY 34Neisseria gonorrhoeae is the sexually transmitted bacterial pathogen responsible for 35 over 100 million cases of gonorrhea worldwide each year. The incidence of reduced susceptibility 36 to the macrolide class antibiotic azithromycin has increased in the past decade; however, a large 37 proportion of the genetic basis of resistance to this drug remains unexplained. Recently, 38 resistance has been shown to be highly associated with mosaic alleles of the multiple transferable 39 resistance (mtr) efflux pump, which have been gained via horizontal gene exchange with other 40
Fecal microbiota transplantation (FMT) is recommended therapy for multiply recurrent Clostridioides difficile infection. Here we report adverse events in seven patients who received FMT linked to a stool donor who was colonized with Shiga toxin-producing Escherichia coli (STEC). No patients died from FMT-transmitted STEC. Improved screening can likely avoid future transmission.
The rate of infection by methicillin-resistant Staphylococcus aureus (MRSA) has declined over the past decade, but it is unclear whether this represents a decline in S. aureus infections overall. To evaluate the trends in the annual rates of infection by S. aureus subtypes and mean antibiotic resistance, we conducted a 15-year retrospective observational study at two tertiary care institutions in Boston, MA, of 31,753 adult inpatients with S. aureus isolated from clinical specimens. We inferred the gain and loss of methicillin resistance through genome sequencing of 180 isolates from 2016. The annual rates of infection by S. aureus declined from 2003 to 2014 by 4.2% (2.7% to 5.6%), attributable to an annual decline in MRSA of 10.9% (9.3% to 12.6%). Penicillin-susceptible S. aureus (PSSA) increased by 6.1% (4.2% to 8.1%) annually, and rates of methicillin-susceptible penicillin-resistant S. aureus (MSSA) did not change. Resistance in S. aureus decreased from 2000 to 2014 by 0.8 antibiotics (0.7 to 0.8). Within common MRSA clonal complexes, 3/14 MSSA and 2/21 PSSA isolates arose from the loss of resistance-conferring genes. Overall, in two tertiary care institutions in Boston, MA, a decline in S. aureus infections has been accompanied by a shift toward increased antibiotic susceptibility. The rise in PSSA makes penicillin an increasingly viable treatment option.
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