ORCID Profile
0000-0002-4326-2911
Current Organisation
Harvard T.H. Chan School of Public Health
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Cold Spring Harbor Laboratory
Date: 08-01-2020
DOI: 10.1101/2020.01.07.896696
Abstract: 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 ( %) 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 = 9.90×10 −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.
Publisher: Cold Spring Harbor Laboratory
Date: 13-02-2020
DOI: 10.1101/2020.02.12.946533
Abstract: Genotype-based diagnostics for antibiotic resistance represent a promising alternative to empiric therapy, reducing inappropriate and ineffective antibiotic use. However, because such assays infer resistance phenotypes based on the presence or absence of known genetic markers, their utility will wane in response to the emergence of novel resistance. Maintenance of these diagnostics will therefore require surveillance designed to ensure early detection of novel resistance variants, but efficient strategies to do so remain to be defined. Here, we evaluate the efficiency of targeted s ling approaches informed by patient and pathogen characteristics in detecting genetic variants associated with antibiotic resistance or diagnostic escape in Neisseria gonorrhoeae , focusing on this pathogen because of its high burden of disease, the imminent threat of treatment resistance, and the use and ongoing development of genotype-based diagnostics. We show that incorporating patient characteristics, such as demographics, geographic regions, or anatomical sites of isolate collection, into s ling approaches is not a reliable strategy for increasing variant detection efficiency. In contrast, s ling approaches informed by pathogen characteristics, such as genomic ersity and genomic background, are significantly more efficient than random s ling in identifying genetic variants associated with antibiotic resistance and diagnostic escape.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2020
DOI: 10.1038/S41467-020-17980-1
Abstract: 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.
Location: United States of America
No related grants have been discovered for Kevin Ma.