Discovery and Structure-Based Optimization of 2‑Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors

We
are concerned with the development of novel anti-infectives
with dual antibacterial and antiretroviral activities for MRSA/HIV-1
co-infection. To achieve this goal, we exploited for the first time
the mechanistic function similarity between the bacterial RNA polymerase
(RNAP) “switch region” and the viral non-nucleoside
reverse transcriptase inhibitor (NNRTI) binding site. Starting from
our previously discovered RNAP inhibitors, we managed to develop potent
RT inhibitors effective against several resistant HIV-1 strains with
maintained or enhanced RNAP inhibitory properties following a structure-based
design approach. A quantitative structure–activity relationship
(QSAR) analysis revealed distinct molecular features necessary for
RT inhibition. Furthermore, mode of action (MoA) studies revealed
that these compounds inhibit RT noncompetitively, through a new mechanism
via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors
are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against
NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds
showed only marginal cytotoxicity.