scholarly journals High-Level Azithromycin Resistance Occurs in Neisseria gonorrhoeae as a Result of a Single Point Mutation in the 23S rRNA Genes

2010 ◽  
Vol 54 (9) ◽  
pp. 3812-3816 ◽  
Author(s):  
Stephanie A. Chisholm ◽  
Jayshree Dave ◽  
Catherine A. Ison
Keyword(s):  
United Kingdom ◽  
Neisseria Gonorrhoeae ◽  
Point Mutation ◽  
Single Point ◽  
23S Rrna ◽  
Single Point Mutation ◽  
The United Kingdom ◽  
High Level ◽  
Domain V ◽  
Azithromycin Resistance

ABSTRACT High-level azithromycin resistance (AZM-HR), defined as a MIC of ≥256 mg/liter, emerged in Neisseria gonorrhoeae in the United Kingdom in 2004. To determine the mechanism of this novel phenotype, isolates from the United Kingdom that were AZM-HR (n, 19), moderately AZM resistant (MICs, 2 to 8 mg/liter) (n, 26), or sensitive (MICs, 0.12 to 0.25 mg/liter) (n, 4) were screened for methylase (erm) genes and for mutations in the mtrR promoter region, associated with efflux pump upregulation. All AZM-resistant isolates and 12 sensitive isolates were screened for mutations in domain V of each 23S rRNA allele. All AZM-HR isolates contained the A2059G mutation (Escherichia coli numbering) in three (3 isolates) or four (16 isolates) 23S rRNA alleles. Most (22/26) moderately AZM resistant isolates contained the C2611T mutation in at least 3/4 alleles. The remainder contained four wild-type alleles, as did 8/12 sensitive isolates, while one allele was mutated in the remaining four sensitive isolates. Serial passage of AZM-sensitive colonies on an erythromycin-containing medium selected AZM-HR if the parent strain already contained mutation A2059G in one 23S rRNA allele. The resultant AZM-HR strains contained four mutated alleles. Eight isolates (five moderately AZM resistant and three AZM-HR) contained mutations in the mtrR promoter. No methylase genes were detected. This is the first evidence that AZM-HR in gonococci may result from a single point mutation (A2059G) in the peptidyltransferase loop in domain V of the 23S rRNA gene. Mutation of a single allele is insufficient to confer AZM-HR, but AZM-HR can develop under selection pressure. The description of a novel resistance mechanism will aid in screening for the AZM-HR phenotype.

scholarly journals High-Level Chromosomally Mediated Tetracycline Resistance in Neisseria gonorrhoeae Results from a Point Mutation in the rpsJ Gene Encoding Ribosomal Protein S10 in Combination with the mtrR and penB Resistance Determinants

2005 ◽  
Vol 49 (10) ◽  
pp. 4327-4334 ◽  
Author(s):  
Mei Hu ◽  
Sobhan Nandi ◽  
Christopher Davies ◽  
Robert A. Nicholas
Keyword(s):  
Amino Acids ◽  
Neisseria Gonorrhoeae ◽  
Ribosomal Protein ◽  
Point Mutation ◽  
Single Point ◽  
Ribosomal Subunit ◽  
Tetracycline Resistance ◽  
Saturation Mutagenesis ◽  
Single Point Mutation ◽  
High Level

ABSTRACT Neisseria gonorrhoeae becomes resistant to tetracycline by two major mechanisms: expression of a plasmid-encoded TetM protein and mutations in endogenous genes (chromosomally mediated resistance). Early studies by Sparling and colleagues (P. F. Sparling F. A. J. Sarubbi, and E. Blackman, J. Bacteriol. 124:740-749, 1975) demonstrated that three genes were involved in high-level chromosomally mediated tetracycline resistance (MIC of tetracycline ≥ 2 μg/ml): ery-2 (now referred to as mtrR), penB, and tet-2. While the identities of the first two genes are known, the tet-2 gene has not been identified. We cloned the tet-2 gene, which confers tetracycline resistance, from tetracycline-resistant clinical isolate N. gonorrhoeae FA6140 and show that resistance is due to a single point mutation (Val-57 to Met) in the rpsJ gene (rpsJ1) encoding ribosomal protein S10. Moreover, the identical mutation was found in six distinct tetracycline-resistant clinical isolates in which the MIC of tetracycline was ≥2 μg/ml. Site-saturation mutagenesis of the codon for Val-57 identified two other amino acids (Leu and Gln) that conferred identical levels of resistance as the Met-57 mutation. The mutation maps to the vertex of a loop in S10 that is near the aminoacyl-tRNA site in the structure of the 30S ribosomal subunit from Thermus thermophilus, and the residue equivalent to Val-57 in T. thermophilus S10, Lys-55, is within 8 to 9 Å of bound tetracycline. These data suggest that large noncharged amino acids alter the rRNA structure near the tetracycline-binding site, leading to a lower affinity of the antibiotic.

scholarly journals Molecular pathways to high-level azithromycin resistance in Neisseria gonorrhoeae

2021 ◽  
Author(s):  
J G E Laumen ◽  
S S Manoharan-Basil ◽  
E Verhoeven ◽  
S Abdellati ◽  
I De Baetselier ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Ribosomal Proteins ◽  
Efflux Pump ◽  
23S Rrna ◽  
Rrna Gene ◽  
23S Rrna Gene ◽  
Evolution Of Resistance ◽  
High Level ◽  
Azithromycin Resistance ◽  
Level Resistance

Abstract Background The prevalence of azithromycin resistance in Neisseria gonorrhoeae is increasing in numerous populations worldwide. Objectives To characterize the genetic pathways leading to high-level azithromycin resistance. Methods A customized morbidostat was used to subject two N. gonorrhoeae reference strains (WHO-F and WHO-X) to dynamically sustained azithromycin pressure. We tracked stepwise evolution of resistance by whole genome sequencing. Results Within 26 days, all cultures evolved high-level azithromycin resistance. Typically, the first step towards resistance was found in transitory mutations in genes rplD, rplV and rpmH (encoding the ribosomal proteins L4, L22 and L34 respectively), followed by mutations in the MtrCDE-encoded efflux pump and the 23S rRNA gene. Low- to high-level resistance was associated with mutations in the ribosomal proteins and MtrCDE efflux pump. However, high-level resistance was consistently associated with mutations in the 23S ribosomal RNA, mainly the well-known A2059G and C2611T mutations, but also at position A2058G. Conclusions This study enabled us to track previously reported mutations and identify novel mutations in ribosomal proteins (L4, L22 and L34) that may play a role in the genesis of azithromycin resistance in N. gonorrhoeae.

scholarly journals New Mutation in 23S rRNA Gene Associated with High Level of Azithromycin Resistance in Neisseria gonorrhoeae

2010 ◽  
Vol 54 (4) ◽  
pp. 1652-1653 ◽  
Author(s):  
Patricia G. Galarza ◽  
Raquel Abad ◽  
Liliana Fernández Canigia ◽  
Luis Buscemi ◽  
Irene Pagano ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
23S Rrna ◽  
Rrna Gene ◽  
New Mutation ◽  
23S Rrna Gene ◽  
High Level ◽  
Azithromycin Resistance

scholarly journals Detection in the United Kingdom of the Neisseria gonorrhoeae FC428 clone, with ceftriaxone resistance and intermediate resistance to azithromycin, October to December 2018

2019 ◽  
Vol 24 (10) ◽  
Author(s):  
David W Eyre ◽  
Katy Town ◽  
Teresa Street ◽  
Leanne Barker ◽  
Nicholas Sanderson ◽  
...  
Keyword(s):  
United Kingdom ◽  
Neisseria Gonorrhoeae ◽  
Whole Genome ◽  
Drug Resistant ◽  
Genome Sequences ◽  
Sexual Network ◽  
The United Kingdom ◽  
Intermediate Resistance ◽  
Azithromycin Resistance ◽  
Urgent Action

We describe detection in the United Kingdom (UK) of the drug-resistant Neisseria gonorrhoeae FC428 clone, with ceftriaxone resistance and intermediate azithromycin resistance. Two female patients developed infection following contact with UK-resident men from the same sexual network linked to travel to Ibiza, Spain. One case failed treatment with ceftriaxone, and azithromycin and gentamicin, before successful treatment with ertapenem. Both isolates had indistinguishable whole-genome sequences. Urgent action is essential to contain this drug-resistant strain.

scholarly journals Molecular pathways to high-level azithromycin resistance in Neisseria gonorrhoeae

2020 ◽  
Author(s):  
J.G.E. Laumen ◽  
S.S. Manoharan-Basil ◽  
E Verhoeven ◽  
S Abdellati ◽  
I De Baetselier ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Ribosomal Proteins ◽  
Efflux Pump ◽  
23S Rrna ◽  
Rrna Gene ◽  
23S Rrna Gene ◽  
Evolution Of Resistance ◽  
High Level ◽  
Azithromycin Resistance ◽  
Level Resistance

AbstractObjectivesThe prevalence of azithromycin resistance in Neisseria gonorrhoeae is increasing in numerous populations worldwide. The aim of this study was to characterize the genetic pathways leading to high-level azithromycin resistance.MethodsA customized morbidostat was used to subject two N. gonorrhoeae reference strains (WHO-F and WHO-X) to dynamically sustained azithromycin pressure. We tracked stepwise evolution of resistance by whole genome sequencing.ResultsWithin 26 days, all cultures evolved high-level azithromycin resistance. Typically, the first step towards resistance was found in transitory mutations in genes rplD, rplV and rpmH (encoding the ribosomal proteins L4, L22 and L34 respectively), followed by mutations in the MtrCDE-encoded efflux pump and the 23S rRNA gene. Low-to high-level resistance was associated with mutations in the ribosomal proteins and MtrCDE-encoded efflux pump. However, high-level resistance was consistently associated with mutations in the 23S ribosomal RNA - mainly the well-known A2059G and C2611T mutations, but also at position A2058G.ConclusionsThis study enabled us to track previously reported mutations and identify novel mutations in ribosomal proteins (L4, L22 and L34) that may play a role in the genesis of azithromycin resistance in N. gonorrhoeae.

scholarly journals Atypical Mutation in Neisseria gonorrhoeae 23S rRNA Associated with High-Level Azithromycin Resistance.

2020 ◽  
Author(s):  
Cau D. Pham ◽  
Evelyn Nash ◽  
Hsi Liu ◽  
Matthew W. Schmerer ◽  
Samera Sharpe ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Genetic Analysis ◽  
Neisseria Gonorrhoeae ◽  
23S Rrna ◽  
Rrna Gene ◽  
Neisseria Gonorrhoea ◽  
23S Rrna Gene ◽  
High Level ◽  
Azithromycin Resistance

A2059G mutation in the 23S rRNA gene is the only reported mechanism conferring high-level azithromycin resistance (HL-AZMR) in Neisseria gonorrhoea. Through U.S. gonococcal antimicrobial resistance surveillance projects, we identified four HL-AZMR gonococcal isolates lacking this mutational genotype. Genetic analysis revealed an A2058G mutation of 23S rRNA alleles in all four isolates. In vitro selected gonococcal strains with homozygous A2058G recapitulated the HL-AZMR phenotype. Taken together, we postulate that A2058G mutation confers HL-AZMR in N. gonorrhoeae.

scholarly journals Genetic relatedness of ceftriaxone-resistant and high-level azithromycin resistant Neisseria gonorrhoeae cases, United Kingdom and Australia, February to April 2018

2019 ◽  
Vol 24 (8) ◽  
Author(s):  
Amy V Jennison ◽  
David Whiley ◽  
Monica M Lahra ◽  
Rikki M Graham ◽  
Michelle J Cole ◽  
...  
Keyword(s):  
United Kingdom ◽  
Neisseria Gonorrhoeae ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Relatedness ◽  
Whole Genome ◽  
The United Kingdom ◽  
High Level

Between February and April 2018, three ceftriaxone-resistant and high-level azithromycin-resistant Neisseria gonorrhoeae cases were identified; one in the United Kingdom and two in Australia. Whole genome sequencing was used to show that the isolates from these cases belong to a single gonococcal clone, which we name the A2543 clone.

scholarly journals Emergence of Neisseria gonorrhoeae Strains Harboring a Novel Combination of Azithromycin-Attenuating Mutations

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Cau D. Pham ◽  
Samera Sharpe ◽  
Karen Schlanger ◽  
Sancta St. Cyr ◽  
Justin Holderman ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Genetic Material ◽  
23S Rrna ◽  
Inhibitory Effects ◽  
Antibiotic Resistant ◽  
Exogenous Dna ◽  
Content Type ◽  
Genomic Plasticity ◽  
High Level ◽  
Azithromycin Resistance

ABSTRACT The nimbleness of Neisseria gonorrhoeae to evade the effect of antibiotics has perpetuated the fight against antibiotic-resistant gonorrhea for more than 80 years. The ability to develop resistance to antibiotics is attributable to its indiscriminate nature in accepting and integrating exogenous DNA into its genome. Here, we provide data demonstrating a novel combination of the 23S rRNA A2059G mutation with a mosaic-multiple transferable resistance (mosaic-mtr) locus haplotype in 14 N. gonorrhoeae isolates with high-level azithromycin MICs (≥256 μg/ml), a combination that may confer more fitness than in previously identified isolates with high-level azithromycin resistance. To our knowledge, this is the first description of N. gonorrhoeae strains harboring this novel combination of resistance determinants. These strains were isolated at two independent jurisdictions participating in the Gonococcal Isolate Surveillance Project (GISP) and in the Strengthening the U.S. Response to Resistant Gonorrhea (SURRG) project. The data suggest that the genome of N. gonorrhoeae continues to shuffle its genetic material. These findings further illuminate the genomic plasticity of N. gonorrhoeae, which allows this pathogen to develop mutations to escape the inhibitory effects of antibiotics.

scholarly journals Gonorrhoea treatment failure caused by a Neisseria gonorrhoeae strain with combined ceftriaxone and high-level azithromycin resistance, England, February 2018

2018 ◽  
Vol 23 (27) ◽  
Author(s):  
David W Eyre ◽  
Nicholas D Sanderson ◽  
Emily Lord ◽  
Natasha Regisford-Reimmer ◽  
Kevin Chau ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Treatment Failure ◽  
Genetic Background ◽  
Spectinomycin Resistance ◽  
The United Kingdom ◽  
Resident Female ◽  
High Level ◽  
First Time ◽  
Azithromycin Resistance ◽  
Urgent Action

We describe a gonorrhoea case with combined high-level azithromycin resistance and ceftriaxone resistance. In February 2018, a heterosexual male was diagnosed with gonorrhoea in the United Kingdom following sexual intercourse with a locally resident female in Thailand and failed treatment with ceftriaxone plus doxycycline and subsequently spectinomycin. Resistance arose from two mechanisms combining for the first time in a genetic background similar to a commonly circulating strain. Urgent action is essential to prevent further spread.

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