Comparative Proteomics of Extended-Spectrum Cephalosporin-Resistant Neisseria gonorrhoeae Isolates Demonstrates Altered Protein Synthesis, Metabolism, Substance Transport, and Membrane Permeability

Abstract

Neisseria gonorrhoeae isolates exhibit resistance to extended-spectrum cephalosporins (ESCs), the last remaining option for first-line empirical monotherapy. Here, we investigated the proteomic profiles of N. gonorrhoeae clinical isolates with ESCresistance to support exploration of the antimicrobial resistance mechanisms for N. gonorrhoeae. We used comparative iTRAQ quantitative proteomics to investigate differential protein expression of three ESC-resistant N. gonorrhoeae clinical isolates using N. gonorrhoeae ATCC49226 as a reference strain. The expression of 40 proteins was downregulated and expression of 56 proteins was upregulated in all three ESCresistant N. gonorrhoeae isolates. Proteins with predicted function of translation, ribosomal structure and biogenesis, as well as components of the Type IV secretory systems, were significantly upregulated. Two differentially expressed proteins of ABC transporters were also reported by other teams in proteomics studies of N. gonorrhoeae isolates under antimicrobial stress conditions. Differentially expressed proteins are involved in energy production and metabolism of carbohydrates and amino acids. Our results indicated that amino acid and carbohydrate metabolism, cell membrane structure, interbacterial DNA transfer, and ribosome components might be involved in mediating ESC-resistance in N. gonorrhoeae. These findings facilitate a better understanding of the mechanisms of ESC-resistance in N. gonorrhoeae and provide useful information for identifying novel targets in the development of antimicrobials against N. gonorrhoeae.

Neisseria Gonorrhoeae infection, current state of antimicrobial susceptibility. literature review

“…So gene/protein mutations cannot entirely explain the mechanism of ESC-resistance in N. gonorrhoeae. 11,[53][54][55][56] Singh A and collaborators, in their 2020 research underpin ESC resistance is conferred by mosaic variants of penicillinbinding protein 2 (PBP2) that have diminished capacity to form acylated adducts with cephalosporins. 57 In the global overview and emerging resistance in which we find ourselves, several proposals arise for the saving of firstline antibiotics against gonococcal infection, such as that put forward by A.K.…”

“…4,5 The disease is associated with high morbidity and socioeconomic consequences 2,4,6 and remaining to be a public health problem worldwide. 3,[7][8][9][10][11] The groups most at risk of acquiring this infection are adolescents, older adults and men who have sex with men (MSM), among others. MSM have been a very important core group since the 1980s, first with the spread of TetM-expressing N gonorrhoeae and, second, with the dissemination of fluoroquinolone-resistant N gonorrhoeae.…”