Azithromycin Resistance and Its Mechanism in Neisseria gonorrhoeae Strains in Hyogo, Japan

Abstract

e Therapeutic options are limited for Neisseria gonorrhoeae infection, especially for oral drugs. The purpose of this study was to investigate the susceptibility of N. gonorrhoeae to oral azithromycin (AZM) and the correlation between AZM resistance-related gene mutations and MIC. We examined the AZM MICs of clinical strains of N. gonorrhoeae, sequenced the peptidyltransferase loop in domain V of 23S rRNA, and investigated the statistical correlation between AZM MIC and the presence and number of the mutations. Among 59 N. gonorrhoeae strains, our statistical data showed that a deletion mutation was seen significantly more often in the higher-MIC group (0.5 g/ml or higher) (35/37; 94.6%) than in the lower-MIC group (0.25 g/ml or less) (4/ 22; 18.2%) (P < 0.0001). However, a mutation of codon 40 (Ala¡Asp) in the mtrR gene (helix-turn-helix) was seen significantly more often in the lower-MIC group (12/22; 54.5%) (P < 0.0001). In N. gonorrhoeae multiantigen sequence typing (NG-MAST) analyses, ST4777 was representative of the lower-MIC group and ST1407, ST6798, and ST6800 were representative of the higher-MIC group. NG-MAST type 1407 was detected as the most prevalent type in AZM-resistant or -intermediate strains, as previously described. In conclusion, a deletion mutation in the mtrR promoter region may be a significant indicator for higher MIC (0.5 g/ml or higher). ST4777 was often seen in the lower-MIC group, and ST1407, ST6798, and ST6800 were characteristic of the higher-MIC group. Further research with a greater number of strains would help elucidate the mechanism of AZM resistance in N. gonorrhoeae infection.

Increasing Resistance to Azithromycin in Neisseria gonorrhoeae in Eastern Chinese Cities: Resistance Mechanisms and Genetic Diversity among Isolates from Nanjing

“…In gonococcal strains with the A-deletion in the 13-bp inverted-repeat sequence of the mtrR promoter (which overlaps the mtrCDE promoter at the −35 region), mtrR expression is abrogated while mtrCDE expression is elevated, most likely because of the greater binding affinity of RNA polymerase for mtrCDE ( 46 ). A report of 59 gonococcal isolates from Japan indicated that the A-deletion in the mtrR promoter was significantly associated with MICs of ≥0.5 mg/liter ( 47 ), a finding similar to that in our study, where >80% of both HL-AZM-R and low- to mid-level AZM-R isolates possessed this A-deletion. Missense mutations in the mtrR gene that result in, for example, a G45D mutation in the helix-turn-helix motif (located at amino acid [aa] 32 to aa 53) in the MtrR repressor can diminish the binding of the repressor to the mtrCDE promoter ( 48 , 49 ).…”

A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics

“…These antibiotics kill bacteria by either inhibiting cell wall synthesis through interacting with penicillin binding proteins (imipenem) or preventing protein synthesis through binding 50S (azithromycin) or 30S subunit (tetracycline and gentamicin) of the ribosome. Imipenem resistance is mainly caused by carbapenemases that degrade -lactam, [32][33][34] azithromycin resistance by methylase that alters the ribosomal target, [35] tetracycline resistance by overexpression of ribosomal protection proteins that remove tetracycline from the ribosome, [36] and gentamicin resistance by aminoglycosidemodifying enzymes. [37,38] A possible reason for reversal of antibiotic resistance phenotype and sensitization of the MDR bacteria toward antibiotic treatment is the polymer's ability in nonspecific binding to cytosolic enzymes (proteins) or genes, including those that are responsible for antibiotic resistance.…”

Azithromycin resistant gonococci: a literature review

“…Similarly according to Wind et al study (2017), exposure to azithromycin was significantly associated with A39T or G45D mtrR mutations. This implies that, frequent azithromycin use in populations at high risk of contracting N. gonorrhoeae induces an increase in minimum inhibitory concentration (MIC), and may result in resistance [ 40 , 49 , 50 ]. A similar study in France also showed that mutations in domain V of 23S rRNA, encoded by the rrl gene, were associated with Azithromycin resistance by gonococcus [ 16 ].…”

“…Shigemura and his research team in Japan likewise reported that a deletion mutation of the mtrR promoter region is a possible mechanism of azithromycin resistance and may be a significant indicator for higher MICs (0.5 μg/ml or higher) in N. gonorrhoeae infection [51]. A recently released data showed a decreased antimicrobial susceptibility of gonococci to azithromycin that may limit effectiveness of the drug [52,53].…”