Molecular mechanism of plasmid-borne resistance to sulfonamide antibiotics

Abstract

The sulfonamides (sulfas) are the oldest class of antibacterial drugs and inhibit the bacterial dihydropteroate synthase (DHPS, encoded by folP), through chemical mimicry of its co-substrate p-aminobenzoic acid (pABA). Resistance to sulfa drugs is mediated either by mutations in folP or acquisition of sul genes, which code for sulfa-insensitive, divergent DHPS enzymes. While the molecular basis of resistance through folP mutations is well understood, the mechanisms mediating sul-based resistance have not been investigated in detail. Here, we determine crystal structures of the most common Sul enzyme types (Sul1, Sul2 and Sul3) in multiple ligand-bound states, revealing a substantial reorganization of their pABA-interaction region relative to the corresponding region of DHPS. We use biochemical and biophysical assays, mutational analysis, and in trans complementation of E. coli ΔfolP to show that a Phe-Gly sequence enables the Sul enzymes to discriminate against sulfas while retaining pABA binding and is necessary for broad resistance to sulfonamides. Experimental evolution of E. coli results in a strain harboring a sulfa-resistant DHPS variant that carries a Phe-Gly insertion in its active site, recapitulating this molecular mechanism. We also show that Sul enzymes possess increased active site conformational dynamics relative to DHPS, which could contribute to substrate discrimination. Our results reveal the molecular foundation for Sul-mediated drug resistance and facilitate the potential development of new sulfas less prone to resistance.

Antibacterial, Cytotoxic and Genotoxic Assessment of New Sulfonamide Derivatives

“…Sulfa drugs work by interacting with the dihydropteroate synthase (DHPS) enzyme and preventing the synthesis of folate, which finally inhibits bacterial cell division. [24] In this study, we showed that the compounds Sul1-5 possess a very important antibacterial activity against Gram negative clinical strains especially against E. coli and K. pneumoniae with very low and interesting MICs values. P. aeruginosa showed a sensibility, only towards tow compounds (Sul1 and Sul4) and S. aureus strains were resistant to these compounds.…”

In Silico Analysis of Mutations in Quinolone Resistance Determinant Region for Flouroquinolone Resistance in <em>Salmonella typhi</em>

“…qnrS1, associated with quinolone resistance, protects DNA gyrase from inhibition by quinolone antibiotics [34]. sul1 and sul2 genes mediate resistance to sulfonamides by encoding di-hydropteroate synthase enzymes [35]. The tetA(B) gene, conferring tetracycline resistance, is associated with efflux pump mechanisms that extrude tetracycline from bacterial cells [36].…”

Antibacterial activity and mechanism of luteolin isolated from Lophatherum gracile Brongn. against multidrug-resistant Escherichia coli

“…The increase in drug resistance has impaired the clinical efficacy of sulfonamides and seriously threatened global public health ( Venkatesan et al, 2023 ). The clinically isolated MDR E. coli is resistant to sulfonamides through gene replacement, that is, obtaining the dihydropteroate synthetase (DHPS) substitutes encoded by the drug resistance genes sul2 and sul3 ( Zhou et al, 2021 ).…”