Inhibition of Class A β-Lactamase (TEM-1) by Narrow Fractions of Humic Substances.

Autor:	Mikhnevich TA; Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1, bld. 3, Moscow 119991, Russia., Vyatkina Turkova AV; Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1, bld. 3, Moscow 119991, Russia., Grigorenko VG; Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1, bld. 3, Moscow 119991, Russia., Rubtsova MY; Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1, bld. 3, Moscow 119991, Russia., Rukhovich GD; Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1, bld. 3, Moscow 119991, Russia., Letarova MA; Vinogradsky Institute of Microbiology, RC Biotechnology of RAS, Prospekt 60-Letiya Oktyabrya, 7, bldg 2, Moscow 117312, Russia., Kravtsova DS; Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1, bld. 3, Moscow 119991, Russia., Vladimirov SA; Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1, bld. 3, Moscow 119991, Russia., Orlov AA; Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, bld. 1, Moscow 121205, Russia., Nikolaev EN; Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, bld. 1, Moscow 121205, Russia., Zherebker A; Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, bld. 1, Moscow 121205, Russia., Perminova IV; Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1, bld. 3, Moscow 119991, Russia.
Jazyk:	angličtina
Zdroj:	ACS omega [ACS Omega] 2021 Sep 07; Vol. 6 (37), pp. 23873-23883. Date of Electronic Publication: 2021 Sep 07 (Print Publication: 2021).
DOI:	10.1021/acsomega.1c02841
Abstrakt:	Antimicrobial resistance is a global threat. The use of biologically active natural products alone or in combination with the clinically proven antimicrobial agents might be a useful strategy to fight the resistance. The scientific hypotheses of this study were twofold: (1) the natural humic substances rich in dicarboxyl, phenolic, heteroaryl, and other fragments might possess inhibitory activity against β-lactamases, and (2) this inhibitory activity might be linked to the molecular composition of the humic ensemble. To test these hypotheses, we used humic substances (HS) from different sources (coal, peat, and soil) and of different fractional compositions (humic acids, hymatomelanic acids, and narrow fractions from solid-phase extraction) for inhibiting serine β-lactamase TEM-1. Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) was used to characterize the molecular composition of all humic materials used in this study. The kinetic assay with chromogenic substrate CENTA was used for assessment of inhibitory activity. The inhibition data have shown that among all humic materials tested, a distinct activity was observed within apolar fractions of hymatomelanic acid isolated from lignite. The decrease in the hydrolysis rate in the presence of most active fractions was 42% (with sulbactam-87%). Of particular importance is that these very fractions caused a synergistic effect (2-fold) for the combinations with sulbactam. Linking the observed inhibition effects to molecular composition revealed the preferential contribution of low-oxidized aromatic and acyclic components such as flavonoid-, lignin, and terpenoid-like molecules. The binding of single low-molecular-weight components to the cryptic allosteric site along with supramolecular interactions of humic aggregates with the protein surface could be considered as a major contributor to the observed inhibition. We believe that fine fractionation of hydrophobic humic materials along with molecular modeling studies on the interaction between humic molecules and β-lactamases might contribute to the development of novel β-lactamase inhibitors of humic nature. Competing Interests: The authors declare no competing financial interest. (© 2021 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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