Applications of genomics to slow the spread of multidrug‐resistant <i>Neisseria gonorrhoeae</i>

Mortimer, Tatum D; Grad, Yonatan H.

doi:10.1111/nyas.13871

Cited by 34 publications

(30 citation statements)

References 174 publications

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“…The linear mixed model adequately controlled for population structure (Supplementary Figure 1), and the proportion of phenotypic MIC variance attributable to genotype (i.e., narrow-sense heritability) estimated by the linear mixed model was high (h 2 = 0.97). In line with this, we observed highly significant unitigs with positive effect sizes corresponding to the known resistance substitutions C2611T and A2059G ( E. coli numbering) in the 23S ribosomal RNA gene as positive controls (Figure 2) 27 . The next most significant variant was a unitig associated with increased susceptibility that mapped to mtrC (β, or effect size, = - 2.80, 95% CI [-3.04, -2.56]; p-value = 3.30×10 -109 ).…”

Section: Microbial Genome-wide Association Identifies a Variant That supporting

confidence: 75%

Increased antibiotic susceptibility inNeisseria gonorrhoeaethrough adaptation to the cervical environment

Mortimer

Hicks

et al. 2020

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28Neisseria gonorrhoeae is an urgent public health threat due to rapidly increasing incidence and 29 antibiotic resistance. In contrast with the trend of increasing resistance, clinical isolates that 30 have reverted to susceptibility regularly appear, prompting questions about which pressures 31 compete with antibiotics to shape gonococcal evolution. Here, we used genome-wide 32 association on the largest collection of N. gonorrhoeae isolates to date (n=4882) to identify loss-33 of-function (LOF) mutations in the efflux pump mtrCDE operon as a mechanism of increased 34 antibiotic susceptibility and demonstrate that these mutations are overrepresented in cervical 35 isolates relative to urethral isolates (odds ratio (OR) = 3.74, 95% CI [1.98-6.70]). In support of a 36 model in which pump expression incurs a fitness cost in this niche, cervical isolates were also 37 enriched relative to urethral isolates in LOF mutations in the mtrCDE activator mtrA (OR = 8.60,) and in farA, a subunit of the FarAB efflux pump (OR = 6.25, 95% CI [3.90-39 9.83]). In total, approximately 1 in 3 cervical isolates (36.4%) contained a LOF mutation in either 40 the efflux pump components mtrC or farA or the activator mtrA. Our findings extend beyond N. 41 gonorrhoeae to other Neisseria: mtrC LOF mutations are rare (<1%) in the primarily 42 nasopharyngeal-colonizing N. meningitidis in a collection of 14,798 genomes but enriched in a 43 heterosexual urethritis-associated lineage (8.6%, p = 9.90×10 -5 ), indicating that efflux pump 44 downregulation contributes broadly to the adaptation of pathogenic Neisseria to the female 45 urogenital tract. Overall, our findings highlight the impact of integrating microbial population 46 genomics with host metadata and demonstrate how host environmental pressures can lead to 47 increased antibiotic susceptibility. 48 49 50 51Neisseria gonorrhoeae is the causative agent of the sexually transmitted disease gonorrhea. 52Antibiotics have played a key role in shaping gonococcal evolution 1-3 , with N. gonorrhoeae 53 gaining resistance to each of the first line antibiotics used to treat it 4-6 . As N. gonorrhoeae is an 54 obligate human pathogen, the mucosal niches it infects-most commonly including the urethra, 55 cervix, pharynx, and rectum-must also influence its evolution 7 . The gonococcal phylogeny 56 suggests the interaction of these factors, with an ancestral split between a relatively drug-57 susceptible lineage circulating primarily in heterosexuals and a relatively drug-resistant lineage 58 circulating primarily in men who have sex with men 3 . 59 60 Despite the deeply concerning increase in antibiotic resistance reported in gonococcal 61 populations globally 8 , some clinical isolates of N. gonorrhoeae have become more susceptible 62 to antibiotics 9,10 . This unexpected phenomenon prompts questions about which environmental 63 pressures could be drivers of increased susceptibility and the mechanisms by which 64 suppression or reversion of resistance may occur. To address these questions, we analy...

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Section: Microbial Genome-wide Association Identifies a Variant That supporting

confidence: 75%

Increased antibiotic susceptibility inNeisseria gonorrhoeaethrough adaptation to the cervical environment

Mortimer

Hicks

et al. 2020

Preprint

Self Cite

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“…In line with this, we observed highly significant unitigs with positive effect sizes corresponding to the known resistance substitutions C2611T and A2059G (E. coli numbering) in the 23S ribosomal RNA gene (Fig. 2) 17 . The next most significant variant was a unitig associated with increased susceptibility that mapped to mtrC (β, or effect size on the log 2 -transformed MIC scale = −2.82, 95% CI [−3.06, −2.57]; p-value = 2.81 × 10 −108 ).…”

Section: Resultssupporting

confidence: 78%

Adaptation to the cervical environment is associated with increased antibiotic susceptibility in Neisseria gonorrhoeae

et al. 2020

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Neisseria gonorrhoeae is an urgent public health threat due to rapidly increasing incidence and antibiotic resistance. In contrast with the trend of increasing resistance, clinical isolates that have reverted to susceptibility regularly appear, prompting questions about which pressures compete with antibiotics to shape gonococcal evolution. Here, we used genome-wide association to identify loss-of-function (LOF) mutations in the efflux pump mtrCDE operon as a mechanism of increased antibiotic susceptibility and demonstrate that these mutations are overrepresented in cervical relative to urethral isolates. This enrichment holds true for LOF mutations in another efflux pump, farAB, and in urogenitally-adapted versus typical N. meningitidis, providing evidence for a model in which expression of these pumps in the female urogenital tract incurs a fitness cost for pathogenic Neisseria. Overall, our findings highlight the impact of integrating microbial population genomics with host metadata and demonstrate how host environmental pressures can lead to increased antibiotic susceptibility.

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“…, in strains with the GyrA S91F mutation). Similarly, as mutations at positions 120 and/or 121 in PorB, the major outer membrane protein in gonococci, have been associated with resistance to a range of drugs from multiple classes 51 , we investigated whether resistance to ESCs is significantly more likely to occur in strains with PorB 120 and/or 121 mutations. Isolates with CRO-RS and CFX-R were significantly more likely to have the GyrA S91F mutation and the PorB G120 and/or A121 mutations than the wild-type GyrA S91 or wild-type PorB G120/A121 ( P < 0.001, Fisher’s exact test, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…For genomic background-aware sampling, isolates were selected at random either limiting the pool to isolates with genotypic ciprofloxacin resistance ( i.e. , the GyrA S91F mutation) or to isolates with a mutation at PorB G120 and/or PorB A121, which have been associated with a range of resistance pathways in multiple classes of antibiotics 51 .…”

Section: Methodsmentioning

confidence: 99%

Targeted surveillance strategies for efficient detection of novel antibiotic resistance variants

Hicks

Kissler

Mortimer

et al. 2020

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20Genotype-based diagnostics for antibiotic resistance represent a promising alternative to 21 empiric therapy, reducing inappropriate and ineffective antibiotic use. However, because 22 103 Results: 104Composition of the datasets. 105The datasets (Table 1) were biased across patient demographics and/or geographic 106 regions (Tables S1 and S2). Isolates from men and men who have sex with men (MSM) 107 were overrepresented in datasets 1 and 2 compared to overall gonorrhea incidence in 108 men and MSM in the US and Australia, respectively, during the study periods (Table S2, 109 P < 0.001 for both datasets by chi-squared test of men vs. women and MSM vs. non-110 MSM in dataset vs. reported incidence). Dataset 4 was comprised exclusively of isolates 111 from men 31 . While it is difficult to estimate the prevalence of pharyngeal gonococcal 112 infections, as they tend to be asymptomatic 32 , pharyngeal isolates represented 4% and 113

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Applications of genomics to slow the spread of multidrug‐resistant Neisseria gonorrhoeae

Cited by 34 publications

References 174 publications

Increased antibiotic susceptibility inNeisseria gonorrhoeaethrough adaptation to the cervical environment

Increased antibiotic susceptibility inNeisseria gonorrhoeaethrough adaptation to the cervical environment

Adaptation to the cervical environment is associated with increased antibiotic susceptibility in Neisseria gonorrhoeae

Targeted surveillance strategies for efficient detection of novel antibiotic resistance variants

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