TABLE 1.

Resistance determinants and mechanisms in Neisseria gonorrhoeae for antimicrobials previously or currently recommended for treatment of gonorrhea

Antimicrobial class	Resistance determinants/mechanisms
Sulfonamides	Oversynthesis of p-aminobenzoic acid, which dilutes the sulfonamide.
	Mutations in folP (encoding the sulfonamide target DHPS) reduce target affinity. The folP mutations comprise SNPs or a mosaic folP gene containing sequences from commensal Neisseria spp.
Penicillins (e.g., penicillin G and ampicillin)	Mutations in penA (encoding the main lethal target PBP2). Traditionally, the mutations were the single amino acid insertion D345 in PBP2 and 4 to 8 concomitant mutations in the PBP2 carboxyl-terminal region, decreasing the PBP2 acylation rate and reducing susceptibility ∼6- to 8-fold. In the last decade, many mosaic penA alleles with up to 70 amino acid alterations, also reducing PBP2 acylation, were described.
	Mutations in mtrR, in the promoter (mainly a single nucleotide [A] deletion in the 13-bp inverted repeat sequence) or coding sequence (commonly a G45D substitution), result in overexpression of and increased efflux from the MtrCDE efflux pump. See the text for rarer mutations resulting in increased MtrCDE efflux.
	porB1b SNPs, e.g., encoding G120K and G120D/A121D mutations in loop 3 of PorB1b, reduce influx (penB resistance determinants). Interestingly, the penB phenotype is apparent only in strains with the mtrR resistance determinant.
	A SNP in pilQ (encoding the pore-forming secretin PilQ of the type IV pili), i.e., E666K, reduces influx. Note that this SNP has been found only in the laboratory and is unlikely to be present in clinical isolates, because it disrupts type IV pilus formation, which is essential for pathogenesis.
	A SNP in ponA (encoding the second penicillin target, PBP1), i.e., “ponA1 determinant” (L421P), reduces penicillin acylation of PBP1 ∼2- to 4-fold.
	“Factor X,” an unknown, nontransformable determinant, increases penicillin MICs ∼3- to 6-fold.
	Penicillinase (TEM-1 or TEM-135)-encoding plasmids, i.e., Asian, African, Toronto, Rio, Nîmes, New Zealand, and Johannesburg plasmids, hydrolyze the cyclic amide bond of the β-lactam ring and render the penicillin inactive.
Tetracyclines (e.g., tetracycline and doxycycline)	A SNP in rpsJ (encoding ribosomal protein S10), i.e., V57M, reduces the affinity of tetracycline for the 30S ribosomal target.
	mtrR mutations (see above).
	penB mutations (see above).
	A SNP in pilQ (see above).
	TetM-encoding plasmids, i.e., American and Dutch plasmids. Evolved derivatives have been described in Uruguay and South Africa. TetM, resembling elongation factor G, binds to the 30S ribosomal subunit and blocks tetracycline target binding.
Spectinomycin	A 16S rRNA SNP, i.e., C1192U, in the spectinomycin-binding region of helix 34, reduces the affinity of the drug for the ribosomal target.
	Mutations in rpsE (encoding the 30S ribosomal protein S5), i.e., the T24P mutation and deletions of V25 and K26E, disrupt the binding of spectinomycin to the ribosomal target.
Quinolones (e.g., ciprofloxacin and ofloxacin)	gyrA SNPs, e.g., S91F, D95N, and D95G, in the QRDR, reduce quinolone binding to DNA gyrase.
	parC SNPs, e.g., D86N, S88P, and E91K, in the QRDR, reduce quinolone binding to topoisomerase IV.
	Many additional mutations in the QRDR of gyrA and parC have been described. An overexpressed NorM efflux pump also slightly enhances quinolone MICs.
Macrolides (e.g., erythromycin and azithromycin)	23S rRNA SNPs, i.e., C2611T and A2059G (in 1 to 4 alleles), result in a 23S rRNA target (peptidyltransferase loop of domain V) with a reduced affinity for the 50S ribosomal macrolide target.
	mtrR mutations (see above).
	erm genes (ermB, ermC, and ermF), encoding rRNA methylases that methylate nucleotides in the 23S rRNA target, block the binding of macrolides.
	MacAB efflux pump; its overexpression increases the MICs of macrolides.
	mef-encoded efflux pump exports macrolides out of the bacterial cell and increases the MICs of macrolides.
Cephalosporins (e.g., ceftibuten, cefpodoxime, cefixime, cefotaxime, and ceftriaxone)	Mosaic penA alleles encoding mosaic PBP2s with a decreased PBP2 acylation rate. These proteins have up to 70 amino acid alterations and are derived from horizontal transfer of partial penA genes from mainly commensal Neisseria spp. Mutations in mosaic PBP2s verified to contribute to resistance are A311V, I312M, V316T, V316P, T483S, A501P, A501V, N512Y, and G545S. The resistance mutations need other epistatic mutations in the mosaic penA allele.
	penA SNPs, i.e., A501V and A501T, in nonmosaic alleles can also enhance cephalosporin MICs. Some additional SNPs (G542S, P551S, and P551L) were statistically associated with enhanced cephalosporin MICs, but their effects remain to be proven with, e.g., site-directed penA mutants in isogenic backgrounds.
	mtrR mutations (see above).
	penB mutations (see above).
	“Factor X,” an unknown, nontransformable determinant (see above).