Penicillin‐binding protein 2 genes of non‐β‐lactamase‐producing, penicillin‐resistant strains of Neisseria gonorrhoeae

Abstract

Oligonucleotides that correspond to regions of the penicillin-binding protein 2 gene (penA) that differ between penicillin-sensitive and penicillin-resistant strains have been used as probes to classify the penA genes in a collection of penicillin-resistant gonococci isolated in Britain. 44/47 of those gonococcal strains that had minimal inhibitory concentrations of greater than or equal to 0.25 microgram benzylpenicillin per ml contained extensively altered penA genes which appeared to be very similar (or identical) to one or other of the two classes of altered penA genes that have been described previously. Since these two classes of altered penA genes are related, it appears that the great majority of the altered penA genes on non-beta-lactamase-producing penicillin-resistant gonococci have a clonal origin. The other three penicillin-resistant strains had altered penA genes that were different to those described previously. A crucial step in the development of the altered forms of PBP2 with decreased affinity for penicillin appears to have been the insertion of an extra codon within the transpeptidase domain of the penA gene. This insertion was found in the penA gene of all gonococci with minimal inhibitory concentrations of greater than 0.016 microgram benzylpenicillin per ml but was not found in any strains with minimal inhibitory concentrations of less than or equal to 0.016 microgram per ml.

Interspecies recombination between the penA genes of Neisseria meningitidis and commensal Neisseria species during the emergence of penicillin resistance in N. meningitidis: natural events and laboratory simulation

“…An additional aspartic acid codon at exactly the same position is found in the penA genes of all penicillinresistant gonococci that have been examined (although in this case the codon is GAC rather than GAT [3,4,12]). The insertion of Asp-345A is known to reduce the affinity of PBP 2 for penicillin and to provide gonococci with increased resistance to the antibiotic (3).…”

Diffusion of Antibiotics through the PilQ Secretin in Neisseria gonorrhoeae Occurs through the Immature, Sodium Dodecyl Sulfate-Labile Form

“…The first resistance determinant acquired by a susceptible strain is the penA allele, which encodes altered forms of penicillinbinding protein 2 (PBP 2), the lethal target of penicillin, with a decreased rate of acylation by penicillin (14,15). While the penA alleles that contribute to high-level penicillin resistance have only 4 to 8 mutations, the recent emergence and spread of strains with intermediate-and high-level resistance to ceftriaxone and cefixime are due in part to the acquisition of highly mosaic alleles of penA with up to 70 amino acid changes that result in markedly lower rates of acylation to expanded-spectrum cephalosporins (9,16).…”

Overexpression of the MtrC-MtrD-MtrE Efflux Pump Due to an mtrR Mutation Is Required for Chromosomally Mediated Penicillin Resistance in Neisseria gonorrhoeae

“…Thus, insertion of an aspartic acid-encoding codon between positions 345 and 346 (3) of the wild-type gene (penA) encoding PBP2 likely arose by horizontal gene exchange between a commensal neisserial species and the gonococcus (26). This mutation reduces the binding affinity of PBP2 for penicillin, which results in decreased (fourfold) susceptibility of gonococci to penicillin (7,25). The Mtr property is due to the action of the MtrC-MtrD-MtrE efflux pump that exports HAs by an energy-dependent process (6,12,13).…”

“…Chromosomally mediated resistance of gonococci to certain antibiotics (e.g., erythromycin, penicillin, and tetracycline) developed in the 1970s because of changes in genes (7,(25)(26)(27) encoding penicillin-binding proteins (PBPs), a mutation termed Mtr (multiple transferable resistance) that enhanced gonococcal resistance to structurally diverse antimicrobial hydrophobic agents (HAs) (12,15), and the replacement of the major outer membrane porin protein (Por) with a similar but antigenically distinct porin (5,10). The molecular basis for these mutations and how they contribute to antimicrobial resistance are now better understood.…”