Substituted salicylic acid analogs offer improved potency against multidrug-resistant Neisseria gonorrhoeae and good selectivity against commensal vaginal bacteria

Abstract

Drug-resistant Neisseria gonorrhoeae represents a major threat to public health; without new effective antibiotics, untreatable gonococcal infections loom as a real possibility. In a previous drug-repurposing study, we reported that salicylic acid had good potency against azithromycin-resistant N. gonorrhoeae. We now report that the anti-gonococcal activity in this scaffold is easily lost by inopportune substitution, but that select substituted naphthyl analogs (3b, 3o and 3p) have superior activity to salicylic acid itself. Furthermore, these compounds retained potency against multiple ceftriaxone- and azithromycin-resistant strains, exhibited rapid bactericidal activity against N. gonorrhoeae, and showed high tolerability to mammalian cells (CC₅₀ > 128 µg/mL). Promisingly, these compounds also show very weak growth inhibition of commensal vaginal bacteria.

Figure 1

Minimum inhibitory concentrations (MICs in µg/mL) of azithromycin (AZM), ceftriaxone, salicylic acid 1a and methyl ester 2a against N. gonorrhoeae CDC-181 (AZM-resistant strain).

Figure 2

Synthesis of 4-chloro derivatives of 3a, 3b, 3j.

Figure 3

Synthesis of additional chlorinated 2-naphthoic acid analogs.

Figure 4

Synthesis of carboxyl derivatives of 3b.

Figure 5

Synthesis of basic or zwitterionic derivatives of 3b.

Figure 6

C5-halogenation of 4-fluorosalicylic acid 1f.

Figure 7

Time-kill kinetics of salicylic acid analogs against N. gonorrhoeae CDC-166. A log-phase bacterial culture was exposed to either compounds 3b, 3o, 3p, 3q, 1i, 1j or azithromycin (at 5 × MIC). DMSO (solvent) served as a negative control. The error bars represent standard deviation values for each test agent.

Figure 8

In vitro cytotoxicity assessment of salicylic acid analogs against kidney epithelial cells (Vero). Compounds were incubated with Vero cells for 24 h. Then, cells were incubated with MTS reagent before measuring absorbance values. Results are presented as percent viable cells relative to DMSO (negative control). The absorbance values represent an average of four samples analyzed for each compound. Error bars represent standard deviation values.