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@ARTICLE{Mikhnevich:180977,
      author       = {T. A. Mikhnevich and V. G. Grigorenko and M. Y. Rubtsova
                      and G. Rukhovich and M. A. Letarova and D. S. Kravtsova and
                      S. A. Vladimirov and A. A. Orlov and E. N. Nikolaev and A.
                      Zherebker and I. V. Perminova},
      othercontributors = {A. V. Vyatkina},
      title        = {{I}nhibition of {C}lass {A} β-{L}actamase ({TEM}-1) by
                      {N}arrow {F}ractions of {H}umic {S}ubstances},
      journal      = {ACS omega},
      volume       = {6},
      number       = {37},
      issn         = {2470-1343},
      address      = {Washington, DC},
      publisher    = {ACS Publications},
      reportid     = {DKFZ-2022-01702},
      pages        = {23873 - 23883},
      year         = {2021},
      abstract     = {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.},
      ddc          = {660},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1021/acsomega.1c02841},
      url          = {https://inrepo02.dkfz.de/record/180977},
}