Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea

Abstract

The new superbug Neisseria gonorrhoeae has retained resistance to antimicrobials previously recommended for first-line treatment and has now demonstrated its capacity to develop resistance to the extended-spectrum cephalosporin, ceftriaxone, the last remaining option for first-line empiric treatment of gonorrhea. An era of untreatable gonorrhea may be approaching, which represents an exceedingly serious public health problem. Herein, we review the evolution, origin and spread of antimicrobial resistance and resistance determinants (with a focus on extended-spectrum cephalosporins) in N. gonorrhoeae, detail the current situation regarding verified treatment failures with extended-spectrum cephalosporins and future treatment options, and highlight essential actions to meet the large public health challenge that arises with the possible emergence of untreatable gonorrhea. Essential actions include: implementing action/response plans globally and nationally; enhancing surveillance of gonococcal antimicrobial resistance, treatment failures and antimicrobial use/misuse; and improving prevention, early diagnosis and treatment of gonorrhea. Novel treatment strategies, antimicrobials (or other compounds) and, ideally, a vaccine must be developed.

Figure 1. An illustration of the known resistance determinants responsible for decreased susceptibility and resistance to extended-spectrum cephalosporins in Neisseria gonorrhoeae

penA encodes altered forms of PBP2, the lethal target for β-lactam antimicrobials. The purple spheres indicate amino acid alterations in a mosaic PBP2 compared with wild-type PBP2. Expression of mtrR results in overexpression of the MtrC–MtrD–MtrE efflux pump and activation of penB. penB encodes mutations in the major outer membrane porin (PorB1b) that decrease influx of antimicrobials. ponA, encoding an altered form of PBP1, has been demonstrated to be involved in penicillin resistance, but not yet in resistance to extended-spectrum cephalosporins. The structure of PBP2 is from Neisseria gonorrhoeae. The other structures are from closely related structures in other bacteria, that is, the MtrCDE are of AcrAB-TolC from Escherichia coli; the structure of PorB1b is of Neisseria meningitidis PorB and the structure of PBP1 is of E. coli PBP1b. The PDB codes are: 2f1M (AcrA), 1IWG (AcrB), 1EK9 (TolC), 3A2R (PorB), 3FWM (PBP1) and 3EQU (PBP2).

Figure 2. The structure of PBP2 from Neisseria gonorrhoeae

The C-terminal domain (transpeptidase domain) with the active site for binding of β-lactam antimicrobials is at the top and the N-terminal domain (structural domain) that anchors PBP2 to the cytoplasmic membrane at the bottom. The structure is color-ramped blue-to-red in the N-terminal to C-terminal direction.

Figure 3. Crystal structure of PBP2 displaying all amino acids currently verified to be involved in enhancing the MICs of extended-spectrum cephalosporins

(A) Location of the G545S mutation and the β-lactam active site sequence motifs at the crystal structure of PBP2. The interactions of Thr498 and Thr500 within the KTG(T) active site motif with the main chain amides of Gly545 and Gly546 are illustrated. Mutation of Gly545 to Ser incorporates a hydroxylated side chain that potentially could perturb the interactions between the two Thr residues on β3 and the main chain of the α11 helix [81]. The SxxK active site motif is also shown. (B) The crystal structure of PBP2 showing the location of all amino acid alterations (with the exception of G545S shown in A) currently verified to increase the MICs of extended-spectrum cephalosporins. Ile312 and Val316 are located on the opposite side of Ser310 and Lys313 of the SxxK active site motif on the α2 helix and pack into a hydrophobic pocket. Mutation to larger (I312M) or more hydrophilic (V316T) side chains might disrupt these interactions and alter the position of the SxxK active site motif. N512 is relatively distant from the active site on the β3–β4 loop and it is possible that the N512Y alteration perturbs the architecture of the KTG active site motif of the β3 strand [81]. Replacement of the methyl side chain of A501, which is located on the β3–β4 loop close to the KTG active site motif, with the more bulky side chains of valine (A501V), threonine (A501T) or proline (A501P) might inhibit the binding of extended-spectrum cephalosporins by clashing with their R1 substituents [25,81]. The novel A311V and T316S alterations, which are in close proximity to the β-lactam active site, appear to contribute to high-level resistance to extended-spectrum cephalosporins [23]. Elucidation of their effects in detail is in progress. Images were created in PyMol and were adapted from [81].