Identification of the Target for a Transition Metal-α-Amino Acid Complex Antibiotic Against Mycobacterium smegmatis

George W Karpin; Joseph S Merola; Joseph O Falkinham 3rd

doi:10.3389/fphar.2021.686358

Identification of the Target for a Transition Metal-α-Amino Acid Complex Antibiotic Against Mycobacterium smegmatis

Front Pharmacol. 2021 Jun 25:12:686358. doi: 10.3389/fphar.2021.686358. eCollection 2021.

Authors

George W Karpin^{1

2}, Joseph S Merola^{1

2}, Joseph O Falkinham 3rd^{1

3}

Affiliations

¹ Virginia Tech Center for Drug Discovery and Development, Blacksburg, VA, United States.
² Department of Chemistry, Virginia Tech, Blacksburg, VA, United States.
³ Department of Biological Sciences, Virginia Tech, Blacksburg, VA, United States.

Abstract

Spontaneous mutants of Mycobacterium smegmatis strain mc²155 resistant to 1-PG (iridium-L-phenylglycine complex), an antimycobacterial antibiotic, were isolated. Based on the discovery that some 1-PG-resistant mutants (1-PG ^R ) were also resistant to high concentrations of clarithromycin (≥250 μg/ml), but no other anti-mycobacterial antibiotics, the 23S rRNA region spanning the peptidyl transferase domain was sequenced and mutations shown to be localized in the peptidyl transferase domain of the 23S rRNA gene. Measurements showed that 1-PG bound to ribosomes isolated from the 1-PG-sensitive parental strain, but the ribosome binding values for the 1-PG ^R mutant reduced.

Keywords: 23S rRNA; clarithromycin; mycobacteria; peptidyl transferase; transition metal-α-amino acid complexes.