A Small Molecule Substrate Mimic to Inhibit Bacterial Hsp70 Chaperone Function

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Given the rapid spread of antibiotic resistance worldwide, it is imperative to develop new strategies against pathogenic bacteria. Here, we report a small-molecule inhibitor of bacterial heat shock protein 70 (Hsp70), called DnaK, a central component of the bacterial protein chaperone network. Screening of an in-house pyridylamide-based peptidomimetic library identified M7 as an inhibitor of DnaK ATPase and substrate refolding activity with intrinsic fluorescence properties. Mechanistic studies revealed that M7 likely engages the substrate-binding pocket of DnaK. Treatment of bacterial cells with M7 led to the accumulation of σ-32, without affecting protein translation, consistent with impaired DnaK function. Microscopy images of Escherichia coli AS19 cells treated with M7 revealed filamentous growth, a phenotypic defect consistent with compromised DnaK function. Moreover, M7 effectively inhibited the growth of E. coli AS19 and some Gram-positive bacteria, including Staphylococcus aureus and Bacillus cereus. These findings highlight a promising class of peptidomimetic DnaK inhibitors as potential antibacterial agents, as well as a chemical biology tool to interrogate the broader network of chaperone-mediated protein folding.

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