The RNA Polymerase Inhibitor Corallopyronin A Has a Lower Frequency of Resistance Than Rifampicin in Staphylococcus aureus

Corallopyronin A (CorA) is active against Gram-positive bacteria and targets the switch region of RNA polymerase. Because of the high frequency of mutation (FoM) leading to rifampicin resistance, we determined the CorA FoM in S. aureus using fluctuation analysis at 4 × minimum inhibitory concentrati...

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Published in:Antibiotics (Basel) 2022-07, Vol.11 (7), p.920
Main Authors: Balansky, Jan, Pfarr, Kenneth, Szekat, Christiane, Kehraus, Stefan, Aden, Tilman, Grosse, Miriam, Jansen, Rolf, Hesterkamp, Thomas, Schiefer, Andrea, König, Gabriele M, Stadler, Marc, Hoerauf, Achim, Bierbaum, Gabriele
Format: Article
Language:English
Subjects:
Amino acids
Antibiotics
Bacteria
Corallopyronin A
DNA-directed RNA polymerase
E coli
Experiments
Gram-positive bacteria
Minimum inhibitory concentration
Mutagenesis
Mutation
mutation frequency
mutation rate
Mutation rates
natural product
Resistant mutant
rifampicin
Rifampin
RNA polymerase
RpoB protein
Staphylococcus aureus
Strains (organisms)
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Summary:Corallopyronin A (CorA) is active against Gram-positive bacteria and targets the switch region of RNA polymerase. Because of the high frequency of mutation (FoM) leading to rifampicin resistance, we determined the CorA FoM in S. aureus using fluctuation analysis at 4 × minimum inhibitory concentration (MIC). Resistant mutants were characterized. S. aureus strains HG001, Mu50, N315, and USA300 had an MIC of 0.25 mg/L. The median FoM for CorA resistance was 1.5 × 10−8, 4.5-fold lower than the median FoM of 6.7 × 10−8 for rifampicin, and was reflected in a 4-fold lower mutation rate for CorA than rifampicin (6 × 10−9 for CorA vs. 2.5 × 10−8 for rifampicin). In CorA-resistant/rifampicin-sensitive strains, the majority of amino acid exchanges were S1127L in RpoB or K334N in RpoC. S. aureus Mu50, a rifampicin-resistant clinical isolate, yielded two further exchanges targeting amino acids L1131 and E1048 of the RpoB subunit. The plating of >1011 cells on agar containing a combination of 4 × MIC of rifampicin and 4 × MIC of CorA did not yield any growth. In conclusion, with proper usage, e.g., in combination therapy and good antibiotic stewardship, CorA is a potential antibiotic for treating S. aureus infections.
ISSN:2079-6382
2079-6382
DOI:10.3390/antibiotics11070920