Mutational Diversity in the Quinolone Resistance-Determining Regions of Type-II Topoisomerases of Salmonella Serovars

Abstract

Quinolone resistance in bacterial pathogens has primarily been associated with mutations in the quinolone resistance-determining regions (QRDRs) of bacterial type-II topoisomerases, which are DNA gyrase and topoisomerase IV. Depending on the position and type of the mutation (s) in the QRDRs, bacteria either become partially or completely resistant to quinolone. QRDR mutations have been identified and characterized in Salmonella enterica isolates from around the globe, particularly during the last decade, and efforts have been made to understand the propensity of different serovars to carry such mutations. Because there is currently no thorough analysis of the available literature on QRDR mutations in different Salmonella serovars, this review aims to provide a comprehensive picture of the mutational diversity in QRDRs of Salmonella serovars, summarizing the literature related to both typhoidal and non-typhoidal Salmonella serovars with a special emphasis on recent findings. This review will also discuss plasmid-mediated quinolone-resistance determinants with respect to their additive or synergistic contributions with QRDR mutations in imparting elevated quinolone resistance. Finally, the review will assess the contribution of membrane transporter-mediated quinolone efflux to quinolone resistance in strains carrying QRDR mutations. This information should be helpful to guide the routine surveillance of foodborne Salmonella serovars, especially with respect to their spread across countries, as well as to improve laboratory diagnosis of quinolone-resistant Salmonella strains.

Keywords: DNA gyrase; Salmonella; fluoroquinolones; food-borne pathogens; non-typhoidal Salmonella (NTS); plasmid-mediated quinolone resistance (PMQR); quinolone resistance-determining regions (QRDRs); topoisomerase IV; typhoidal Salmonella.

Figure 1

Structures of the quinolone, naphthyridone, and fluoroquinolone nuclei. ‘R’ denotes an alkyl group, ‘X’ denotes a small substituent, such as F, Cl, or CH3O⁻.

Figure 2

Amino acid sequence alignment for the QRDR of E. coli, S. Typhi and S. Typhimurium homologs. (A); GyrA QRDR (Ala67-Gln106) (B); GyrB QRDR (Asp426-Lys447) (C); ParC QRDR (Ala64 to Gln103) (D); ParE QRDR (Asp420-Lys441). The alignment was performed with MUSCLE using Jalview [23]. The complete sequence alignment of all these genes is shown in supplementary Figures S1–S4 for GyrA, GyrB, ParC, and ParE, respectively.

Figure 3

Mutations found in the QRDRs of DNA gyrase (GyrA and GyrB) and topoisomerase IV (ParC and ParE) of typhoidal Salmonella.

Figure 4

Summary of mutations found in GyrA. Red boxes indicate residues found to be mutated in typhoidal Salmonella. Black boxes indicate residues found to be mutated in non-typhoidal Salmonella (discussed below) and “*” indicate residues found to be mutated in both.

Figure 5

Summary of mutations found in GyrB. Red boxes indicate residues found to be mutated in typhoidal Salmonella. Black boxes indicate residues found to be mutated in non-typhoidal Salmonella (discussed below) and “*” indicate residues found to be mutated in both.

Figure 6

Summary of mutations found in ParC. Red boxes indicate residues found to be mutated in typhoidal Salmonella. Black boxes indicate residues found to be mutated in non-typhoidal Salmonella (discussed below) and “*” indicate residues found to be mutated in both.

Figure 7

Summary of mutations found in ParE. Red boxes indicate residues found to be mutated in typhoidal Salmonella. Black boxes indicate residues found to be mutated in non-typhoidal Salmonella (discussed below).

Figure 8

Mutations in the QRDRs of NTS.