Mutations in Neisseria gonorrhoeae grown in sub-lethal concentrations of monocaprin do not confer resistance.

Colin P Churchward,Alan Calder,Lori A S Snyder,William M Shafer

doi:10.1371/journal.pone.0195453

Abstract

Neisseria gonorrhoeae, due to its short lipooligosaccharide structure, is generally more sensitive to the antimicrobial effects of some fatty acids than most other Gram negative bacteria. This supports recent development of a fatty acid-based potential treatment for gonococcal infections, particularly ophthalmia neonatorum. The N. gonorrhoeae genome contains genes for fatty acid resistance. In this study, the potential for genomic mutations that could lead to resistance to this potential new treatment were investigated. N. gonorrhoeae strain NCCP11945 was repeatedly passaged on growth media containing a sub-lethal concentration of fatty acid myristic acid and monoglyceride monocaprin. Cultures were re-sequenced and assessed for changes in minimum inhibitory concentration. Of note, monocaprin grown cultures developed a mutation in transcription factor gene dksA, which suppresses molecular chaperone DnaK and may be involved in the stress response. The minimum inhibitory concentration after exposure to monocaprin showed a modest two-fold change. The results of this study suggest that N. gonorrhoeae cannot readily evolve resistance that will impact treatment of ophthalmia neonatorum with monocaprin.

Highlights

Monocaprin is a powerful fast-acting bactericidal agent against Neisseria gonorrhoeae [1,2]
The purpose of this study was to identify genomic mutations that resulted from passage of N. gonorrhoeae on media containing sub-lethal concentrations of the monoglyceride monocaprin and to determine any changes in the minimum inhibitory concentration (MIC)
It is known that N. gonorrhoeae have an efflux pump-based mechanism of resistance against myristic acid [10,11,12]

Summary

Introduction

Monocaprin is a powerful fast-acting bactericidal agent against Neisseria gonorrhoeae [1,2]. It has recently been proposed as a candidate for treatment of gonococcal eye infections, such as ophthalmia neonatorum, where topical treatment would rapidly kill the bacteria without irritating the eye [2]. Growth of the bacteria on media containing a sub-lethal concentration of the antimicrobial will select for genomic mutations that confer an addition level of fitness in this environment to out-compete non-mutated cells. N. gonorrhoeae has been passaged on media containing increasing amounts of the fluoroquinolone ciprofloxacin, resulting in an isolate that had 10,000 times greater resistance than the parental isolate [3].

Objectives

Methods

Results