Design, Synthesis, and Biological Evaluation of 1,3,4-Thiadiazole Derivatives as Novel Potent Peptide Deformylase Inhibitors for Combating Drug-Resistant Gram-Positive and -Negative Bacteria

The
prevalence of drug-resistant bacteria is a major challenge
throughout the world, especially with respect to Gram-negative bacteria,
such as drug-resistant Acinetobacter baumannii, which are regarded as the greatest bacterial threat to human health
by the World Health Organization (WHO). In this work, 1,3,4-thiadiazole
was introduced into the main skeleton of the classical peptidomimetic
peptide deformylase (PDF) inhibitor in pursuit of highly efficient
and broad-spectrum bacteriostatic drugs. Upon detailed structure–activity
relationship study, PDF inhibitors that possess satisfactory activity
against both Gram-positive and Gram-negative bacteria as well as a
lower potential for methemoglobin toxicity were screened out. The
mechanism of the empowered antibacterial activity against Gram-negative
bacteria was also investigated. Finally, for the first time, remarkable
protective efficacy against drug-resistant A. baumannii in a mouse model was achieved by a PDF inhibitor (compound 43). These findings can pave a way to new approaches to the
development of novel broad-spectrum PDF inhibitors.