Biology subjects

Rubin, D. H.

Publications and source records attributed to Rubin, D. H..

5 recordsLinked to original sources

bioRxiv2026

Fluoroquinolone resistance-conferring gyrA variants alter the fitness cost and potentiate the resistance of the zoliflodacin resistance mutation gyrB D429N in Neisseria gonorrhoeae

Neisseria gonorrhoeae is a major public health concern due to its high global prevalence and rapid evolution of antibiotic resistance. A first-in-class topoisomerase inhibitor, zoliflodacin (a spiropyrimidinetrione) recently received FDA approval for treatment of gonorrhea, but its potential for cross-resistance with another topoisomerase inhibitor, the fluoroquinolone antibiotic ciprofloxacin, remains poorly understood. Here, we investigated how genetic diversity in the fluoroquinolone target gyrA influences the resistance and fitness effects of the zoliflodacin resistance mutation gyrBD429N. We constructed an isogenic panel of N. gonorrhoeae to determine how the resistance and fitness effects of the gyrBD429N mutation are modulated by the most common ciprofloxacin resistance-associated variants in gyrA. In the presence of gyrBD429N, the zoliflodacin minimum inhibitory concentration (MIC) was 2-4-fold higher in strains that also contained ciprofloxacin resistance-associated gyrA alleles, and the gyrBD429N mutation reciprocally increased ciprofloxacin MICs of these strains 3-6-fold. Fitness cost of the gyrBD429N mutation varied from modest to severe across gyrA backgrounds, with the largest cost in ciprofloxacin resistant gyrA91F/95G and gyrA91F/95N backgrounds and comparatively minimal cost in the ciprofloxacin resistant gyrA91F/95A background. These results demonstrate the capacity for epistatic interactions among resistance-associated gyrA and gyrB mutations, underscoring the need for genomic surveillance to monitor high-risk combinations of resistance determinants as new therapies are deployed.

microbiology↗

bioRxiv2022

Reemergence of cholera in Haiti

Cholera was absent from Haiti until an inadvertent introduction by United Nations security forces in October 2010. The ensuing epidemic sickened 820,000 and caused 9,792 reported deaths1. The last cholera case in Haiti was recorded in January 2019, and in February 2022, Haiti was declared to have eliminated cholera2. In late September of 2022, a new outbreak began in Port-au-Prince and rapidly expanded to 964 suspected cases by mid-October of which 115 were confirmed by culture.3 Here, we present genomic and phenotypic analysis of the Vibrio cholerae isolated from a stool sample collected on September 30th, 2022 of an index case - a 10-year-old girl who presented with watery diarrhea and severe dehydration - to address the origins of the epidemic.

microbiology↗

bioRxiv2022

Neisseria gonorrhoeae diagnostic escape from a gyrA-based test for ciprofloxacin susceptibility can lead to increased zoliflodacin resistance

The etiologic agent of gonorrhea, Neisseria gonorrhoeae, has become resistant to each of the first line antibiotics used to treat it. However, most isolates in the US remain susceptible to ciprofloxacin, leading to the hypothesis that a diagnostic that accurately reports susceptibility to ciprofloxacin may allow its reintroduction into clinical use. One diagnostic approach is to identify codon 91 in gyrA, where coding for the wildtype serine is associated with ciprofloxacin susceptibility and phenylalanine with resistance. Here, we found that escape from this diagnostic method can occur through gyrA F91S reversion and expansion of pre-existing ciprofloxacin non-susceptible N. gonorrhoeae lineages with gyrA 91S. Furthermore, we found that mutations conferring ciprofloxacin resistance in gyrA 91S isolates led to cross-resistance with zoliflodacin, an antibiotic in phase 3 trial for treatment of gonorrhea. These findings define N. gonorrhoeae mutations that should be monitored via surveillance systems, particularly in populations and regions deploying gyrA 91-based diagnostics, and demonstrate how diagnostics that guide antibiotic therapy can have unintended consequences.

microbiology↗

bioRxiv2022

Variation in supplemental carbon dioxide requirements defines lineage-specific antibiotic resistance acquisition in Neisseria gonorrhoeae

The evolution of the obligate human pathogen Neisseria gonorrhoeae has been shaped by selective pressures from diverse host niche environments1,2 as well as antibiotics3,4. The varying prevalence of antibiotic resistance across N. gonorrhoeae lineages5 suggests that underlying metabolic differences may influence the likelihood of acquisition of specific resistance mutations6,7. We hypothesized that the requirement for supplemental CO2, present in approximately half of isolates8, reflects one such example of metabolic variation. Here, using a genome-wide association study and experimental investigations, we show that CO2-dependence is attributable to a single substitution in a {beta}-carbonic anhydrase, canB. CanB19E is necessary and sufficient for growth in the absence of CO2, and the hypomorphic CanB19G variant confers CO2-dependence. Furthermore, ciprofloxacin resistance is correlated with CanB19G in clinical isolates, and the presence of CanB19G increases the likelihood of acquisition of ciprofloxacin resistance. Together, our results suggest that metabolic variation has impacted the acquisition of fluoroquinolone resistance.

microbiology↗

bioRxiv2020

Increased antibiotic susceptibility in Neisseria gonorrhoeae through adaptation to the cervical environment

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 on the largest collection of N. gonorrhoeae isolates to date (n=4852) 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 isolates relative to urethral isolates (odds ratio (OR) = 3.74, 95% CI [1.98-6.70]). In support of a model in which pump expression incurs a fitness cost in this niche, cervical isolates were also enriched relative to urethral isolates in LOF mutations in the mtrCDE activator mtrA (OR = 8.60, 95% CI [4.96-14.57]) and in farA, a subunit of the FarAB efflux pump (OR = 6.25, 95% CI [3.90-9.83]). In total, approximately 2 in 5 cervical isolates (42.6%) contained a LOF mutation in either the efflux pump components mtrC or farA or the activator mtrA. Our findings extend beyond N. gonorrhoeae to other Neisseria: mtrC LOF mutations are rare (<1%) in the primarily nasopharyngeal-colonizing N. meningitidis in a collection of 14,798 genomes but enriched in a heterosexual urethritis-associated lineage (8.6%, p = 9.90x10-5), indicating that efflux pump downregulation contributes broadly to the adaptation of pathogenic Neisseria to the female urogenital tract. 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.

microbiology↗