As Few as 2 Genetic Loci May Predict Antibiotic Susceptibility in Gonorrhea

Investigators sought to identify a specific set of genetic loci associated with penicillin and tetracycline antibiotic susceptibility among Neisseria gonorrhoeae isolates.

Two genetic loci effectively predicted antibiotic susceptibility to penicillin and tetracycline among Neisseria gonorrhoeae isolates, according to findings published in The Lancet Microbe.

Publicly available whole-genome sequence data from 12,045 clinical N gonorrhoeae isolates with penicillin (n=6935) and tetracycline (n=5727) susceptibility were evaluated for genetic predictors of susceptibility using a genome-wide association analysis. Potential predictive loci (n=1479) were validated using data captured by the Centers for Disease Control and Prevention’s Gonococcal Isolate Surveillance Project. Antibiotic susceptibility was assessed using a minimum inhibitory concentration (MIC) approach, with breakpoint cutoffs of 0.6 µg/mL for penicillin and 0.25 µg/mL for tetracycline susceptibilities.

A unitig of the penA_01 allele without the resistance-associated insertion at codon 345 was significantly associated with penicillin susceptibility (P =5.0´10-14), and a unitig at codon 57 of the wild-type allele rpsJ was associated with tetracycline susceptibility (P =5.6´1016).

The presence of the penA_01 allele combined with the absence of the plasmid-encoded resistance determinant blaTEM predicted susceptibility to penicillin with a specificity of 99.8% and sensitivity of 36.7%. For susceptibility to tetracycline, the wild-type rpsJ codon 57 combined with the absence of the plasmid-encoded resistance determinant tetM had a specificity of 97.2% and specificity of 88.7%.

In the validation dataset, penicillin susceptibility for the predicted loci had a specificity and sensitivity of 98.9% and 63.6% among isolates that were susceptible to penicillin and 100.0% and 4.4% for isolates without resistance, respectively. For tetracycline susceptibility, the predicted loci among resistant isolates had a 94.9% specificity and 78.2% sensitivity, and a 99.5% specificity and 22.1% sensitivity for isolates without resistance.

The investigators found that 88.3% of penicillin isolates that were false negatives had MICs at the breakpoint of 0.06 µg/mL.

Compared with patients from whom the isolates were obtained, susceptible genotypes were more common among men who have sex with women compared with both men who have sex with men and men who have sex with men and women (both P £.0035). Susceptible genotypes were more common among men who were Black, but this finding was not significant after adjustment were made for sex of sexual partners.

This study was limited by its use of an MIC analysis as MIC measurements may vary.

According to the investigators, “the alleles…identified from genomic analyses are promising targets for the development of point-of-care molecular diagnostics for N gonorrhoeae susceptibility to penicillin and tetracycline.”

Disclosure: One author declared affiliations with industry. Please see the original article for a full list of disclosures.


Mortimer TD, Zhang JJ, Ma KC, Grad YH. Loci for prediction of penicillin and tetracycline susceptibility in Neisseria gonorrhoeae: a genome-wide association study. Lancet Microbe. 2022;3(5):E376-E381. doi:10.1016/S2666-5247(22)00034-9