Molecular mechanisms of multidrug resistance in Neisseria gonorrhoeae

Neisseria gonorrhoeae has become a major global health concern due to the increasing multidrug resistance (MDR) which has posed a global health challenge, with current antibiotic treatment options becoming very limited. The MtrCDE efflux pump is a major contributor to the bacterial resistance, as it actively expels the antimicrobial agents. Understanding the impact of efflux pumps, their importance, and the impact of efflux pump mutations on bacterial physiology and resistance is important to develop new therapeutic strategies.

In this study, the effects of mtrCDE disruption were investigated by introducing a targeted mutation in the N. gonorrhoeae strain NCCP11945, creating the ZA1 strain. The mutated strain allowed us to examine the transcriptional and physiological outcome to this efflux pump inactivation.

The effects of the mutation were analysed against novel chemical compounds to evaluate their potential as alternative therapeutic agents. The ZA1 strand provided a unique model for assessing how bacterial resistance mechanisms respond to novel antimicrobial compounds, specifically targeting membrane transport and metabolic pathways. The novel compounds tested were fatty acids, which include nonanoic acid, monocaprin, octanoic acid, oregano oil, and clove oil. These compounds were selected for their known antibacterial and membrane-disrupting properties to assess their effectiveness against N. gonorrhoeae. The findings highlighted the potential for use of fatty acids as antimicrobial agents against multidrug resistant N. gonorrhoeae.

Overall, the investigations showed that disrupting the mtrCDE efflux pump in N. gonorrhoeae strain NCCP11945 triggers extensive compensatory responses, with significant changes in gene expression patterns, including the upregulation of alternative efflux systems, shifts in metabolic pathways, and other alterations. The changes indicated that the loss of the MtrCDE function leads to broad regulatory adaptations. The phenotypic experiments showed that ZA1 exhibited altered antibiotic susceptibility and increased sensitivity to a range of novel compounds including monocaprin, oregano oil, and clove oil.