Antibacterial Marinopyrroles and Pseudilins Act as Protonophores.
Gabriel Castro-Falcón, Jan Straetener, Jan Bornikoel, Daniela Reimer, Trevor N Purdy, Anne Berscheid, Florence M Schempp, Dennis Y Liu, Roger G Linington, Heike Brötz-Oesterhelt, Chambers C Hughes
Author Information
Gabriel Castro-Falcón: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, California 92093, United States.
Jan Straetener: Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen 72076, Germany.
Jan Bornikoel: Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen 72076, Germany.
Daniela Reimer: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, California 92093, United States.
Trevor N Purdy: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, California 92093, United States.
Anne Berscheid: Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen 72076, Germany. ORCID
Florence M Schempp: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, California 92093, United States.
Dennis Y Liu: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
Roger G Linington: Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada. ORCID
Heike Brötz-Oesterhelt: Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen 72076, Germany. ORCID
Chambers C Hughes: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, California 92093, United States. ORCID
Elucidating the mechanism of action (MoA) of antibacterial natural products is crucial to evaluating their potential as novel antibiotics. Marinopyrroles, pentachloropseudilin, and pentabromopseudilin are densely halogenated, hybrid pyrrole-phenol natural products with potent activity against Gram-positive bacterial pathogens like . However, the exact way they exert this antibacterial activity has not been established. In this study, we explore their structure-activity relationship, determine their spatial location in bacterial cells, and investigate their MoA. We show that the natural products share a common MoA based on membrane depolarization and dissipation of the proton motive force (PMF) that is essential for cell viability. The compounds show potent protonophore activity but do not appear to destroy the integrity of the cytoplasmic membrane via the formation of larger pores or interfere with the stability of the peptidoglycan sacculus. Thus, our current model for the antibacterial MoA of marinopyrrole, pentachloropseudilin, and pentabromopseudilin stipulates that the acidic compounds insert into the membrane and transport protons inside the cell. This MoA may explain many of the deleterious biological effects in mammalian cells, plants, phytoplankton, viruses, and protozoans that have been reported for these compounds.
References
J Org Chem. 2010 May 21;75(10):3240-50
[PMID: 20405892]
