Mechanistic link between uptake of sulfonamides and bacteriostatic effect: Model development and application to experimental data from two soil microorganisms

Abstract

Sulfonamides (SA) are antibiotic compounds that are widely used as human and veterinary pharmaceuticals. They are not rapidly biodegradable and have been detected in various environmental compartments. Effects of sulfonamides on microbial endpoints in soil have been reported from laboratory incubation studies. Sulfonamides inhibit the growth of sensitive microorganisms by competitive binding to the dihydropteroate-synthase (DHPS) enzyme of folic acid production. A mathematical model was developed that relates the extracellular SA concentration to the inhibition of the relative bacterial growth rate. Two factors--the anionic accumulation factor (AAF) and the cellular affinity factor (CAF)--determine the effective concentration of an SA. The AAF describes the SA uptake into bacterial cells and varies with both the extra- and intracellular pH values and with the acidic pKa value of an SA. The CAF subsumes relevant cellular and enzyme properties, and is directly proportional to the DHPS affinity constant for an SA. Based on the model, a mechanistic dose-response relationship is developed and evaluated against previously published data, where differences in the responses of Pseudomonas aeruginosa and Panthoea agglomerans toward changing medium pH values were found, most likely as a result of their diverse pH regulation. The derived dose-response relationship explains the pH and pKa dependency of mean effective concentration values (EC50) of eight SA and two soil bacteria based on AAF and CAF values. The mathematical model can be used to extrapolate sulfonamide effects to other pH values and to calculate the CAF as a pH-independent measure for the SA effects on microbial growth.

Oxidation of Sulfonamide Antibiotics of Six-Membered Heterocyclic Moiety by Ferrate(VI): Kinetics and Mechanistic Insight into SO2 Extrusion

“…The variation in the values of k with pH was interpreted quantitatively using acid–base equilibrium of Fe VI and SAs. In the pH range of the study, only monoprotonated and unprotonated species of Fe VI and SAs (X) are involved (eqs and ). ,− The dependence of k on the pH can thus be modeled by eq . where [Fe VI ] tot = [HFeO 4 – ] + [FeO 4 2– ]; [X] tot = [HX] + [X – ]; α i and β j represent the species fractions of Fe VI and selected SA, respectively; i and j are each of the species of Fe VI and selected SA, respectively; and k ij is the species-specific second-order rate constant for the reaction between the Fe VI species i and the X species j . Overall, four reactions could possibly contribute to eq .…”

Ecotoxicological assessment of antibiotics: A call for improved consideration of microorganisms

“…Uptake of antibiotics can also vary as many antibiotics are ionizable. Depending on pH, these antibiotics can exist in neutral or ionized forms, each of which will be taken up by bacteria to a different degree (Focks et al, 2010;Tappe et al, 2008;Zarfl et al, 2008;Zhang et al, 2014). This complexity represents a challenge for ecotoxicological assessment of antibiotic and other chemicals as it may not be possible to obtain a single soil or water type that is optimal for sensitive detection of chemical toxicity.…”

Interactions of 15N-Sulfadiazine and Soil Components As Evidenced by 15N-CPMAS NMR

“…It was already evidenced from literature that the amino group was the main reaction site of SNs, the same site through which SNs bind to intracellular dihydropteroate synthase and exert their bacteriostatic effect. 1,2,42,59 Hence, we used 15 N-amino labeled SDZ to be able to follow changes in the chemical environment of this group through solid-state NMR. Figure 2 shows the background corrected 15 N-CPMAS NMR spectra of the reaction products of 15 N-SDZ with two different HAs in the presence and absence of laccase.…”

“…Sulfonamides (SNs) are the oldest class of synthetic antibiotics in use and act as competitive inhibitors of p -aminobenzoic acid in the folate synthesis in bacteria . Their extensive use in animal husbandry has led to an unintentional widespread occurrence in several environmental compartments like surface waters, ground waters, and soils. − Baran et al estimated that worldwide over 20 000 Mg of SNs are introduced into the biosphere every year.…”