Abstract
Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter pylori is a Gram-negative bacterium that infects about half of the human population and is a major cause of peptic ulcer disease and gastric cancer. Increasing resistance to triple and quadruple H. pylori eradication therapies poses great challenges and urges the development of novel, ideally narrow spectrum, antimicrobials targeting H. pylori. Here, we describe the antimicrobial spectrum of a family of nitrobenzoxadiazol-based antimicrobials initially discovered as inhibitors of flavodoxin: an essential H. pylori protein. Two groups of inhibitors are described. One group is formed by narrow-spectrum compounds, highly specific for H. pylori, but ineffective against enterohepatic Helicobacter species and other Gram-negative or Gram-positive bacteria. The second group includes extended-spectrum antimicrobials additionally targeting Gram-positive bacteria, the Gram-negative Campylobacter jejuni, and most Helicobacter species, but not affecting other Gram-negative pathogens. To identify the binding site of the inhibitors in the flavodoxin structure, several H. pylori-flavodoxin variants have been engineered and tested using isothermal titration calorimetry. An initial study of the inhibitors capacity to generate resistances and of their synergism with antimicrobials commonly used in H. pylori eradication therapies is described. The narrow-spectrum inhibitors, which are expected to affect the microbiota less dramatically than current antimicrobial drugs, offer an opportunity to develop new and specific H. pylori eradication combinations to deal with AMR in H. pylori. On the other hand, the extended-spectrum inhibitors constitute a new family of promising antimicrobials, with a potential use against AMR Gram-positive bacterial pathogens.
Highlights
Helicobacter pylori (H. pylori) is a Gram-negative proteobacterium estimated to infect about 50% of the human population worldwide [1]
We considered that any efflux inhibitors (EIs) had a significant effect on a compound Minimal Inhibitory Concentration (MIC) when this was reduced at least four-fold in the presence of that EI
Against several bacteria from different phyla (Table S2). Their therapeutic activity was reported as the lowest concentration, leading to 50% bacterial growth inhibition in comparison with drug-free controls or as the MIC
Summary
Helicobacter pylori (H. pylori) is a Gram-negative proteobacterium estimated to infect about 50% of the human population worldwide [1]. Hp-Fld [12,13] is an essential protein that mediates the oxidative decarboxylation of pyruvate by pyruvate-oxidoreductase [14] It belongs to the long-chain flavodoxin class, differing from short-chain flavodoxins by the presence of an extra loop that may play a role in the binding to partner proteins [15]. Either long or short-chain, are quite similar at the structural level, Hp-Fld contains a distinct pocket near the binding site of the FMN (flavin mononucleotide) redox cofactor [12]. As the binding of small molecules at such a pocket might serve to inhibit electron transfer by the FMN cofactor or to impair the binding of partner proteins to HpFld [11], a high throughput screening was run to identify flavodoxin binders from a diverse chemical library of 10,000 compounds [16]. By using an in vitro coupled reaction, several binders proved to inhibit Hp-Fld activity and, interestingly, they were subsequently shown to be either bactericidal (three of them) or bacteriostatic for H. pylori
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