title: Mycobacterium tuberculosis is resistant to streptolydigin.
abstract: Drug resistant strains of Mycobacterium tuberculosis (Mtb) undermine tuberculosis (TB) control. Streptolydigin is a broadly effective antibiotic which inhibits RNA polymerase, similarly to rifampicin, a key drug in current TB chemotherapeutic regimens. Due to a vastly improved chemical synthesis streptolydigin and derivatives are being promoted as putative TB drugs. The microplate Alamar Blue assay revealed that Streptococcus salivarius and Mycobacterium smegmatis were susceptible to streptolydigin with minimum inhibitory concentrations (MICs) of 1.6 mg/L and 6.25 mg/L, respectively. By contrast, the MICs of streptolydigin and two derivatives, streptolydiginone and dihydrostreptolydigin, against Mtb were ≥ 100 mg/L demonstrating that Mtb is resistant to streptolydigin in contrast to previous reports. Further, a porin mutant of M. smegmatis is resistant to streptolydigin indicating that porins mediate uptake of streptolydigin across the outer membrane. Since the RNA polymerase is a validated drug target in Mtb and porins are required for susceptibility of M. smegmatis, the absence of MspA-like porins probably contributes to the resistance of Mtb to streptolydigin. This study shows that streptolydigin is not a suitable drug in TB treatment regimens.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, 609 Bevill Biomedical Research Building, 845 19th Street South, Birmingham, AL 35294, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Speer
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Rowland
authors.forename: Michael
authors.initials: M
authors.lastname: Niederweis
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry / Q000494:pharmacology*; D000904:Antibiotics, Antitubercular / Q000737:chemistry / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000502:physiology; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D018272:Porins / Q000235:genetics / Q000502:physiology
chemical_list: D000617:Aminoglycosides; D000904:Antibiotics, Antitubercular; D018272:Porins; C100307:streptolydigin; D012321:DNA-Directed RNA Polymerases