Reassessment of the genetic basis of natural rifampin resistance in the genus Rickettsia

• Published in: MicrobiologyOpen (Weinheim) 2024-08, Vol.13 (4), p.e1431-n/a
• Main Authors: Amoros, Julien, Fattar, Noor, Buysse, Marie, Louni, Meriem, Bertaux, Joanne, Bouchon, Didier, Duron, Olivier
• Format: Article
• Language: English
• Subjects: Acid resistance; Amino acids; Anti-Bacterial Agents - pharmacology; Antibiotics; Arachnids; Bacteria; Bacterial infections; Detoxification; DNA-directed RNA polymerase; DNA-Directed RNA Polymerases - genetics; Drug Resistance, Bacterial - genetics; Efflux; Evolutionary genetics; Genome, Bacterial - genetics; Humans; Laboratories; Leucine; Life Sciences; Microbial Sensitivity Tests; Mutation; natural antibiotic resistance; Original; Phylogeny; Residues; Ribonucleic acid; Rickettsia; Rickettsia - drug effects; Rickettsia - genetics; Rifampin; Rifampin - pharmacology; RNA; RNA polymerase; RNA polymerase β subunit; rpoB; Species; Typhus
• ISSN: 2045-8827; 2045-8827
• DOI: 10.1002/mbo3.1431

Rickettsia, a genus of obligate intracellular bacteria, includes species that cause significant human diseases. This study challenges previous claims that the Leucine‐973 residue in the RNA polymerase beta subunit is the primary determinant of rifampin resistance in Rickettsia. We investigated a previously untested Rickettsia species, R. lusitaniae, from the Transitional group and found it susceptible to rifampin, despite possessing the Leu‐973 residue. Interestingly, we observed the conservation of this residue in several rifampin‐susceptible species across most Rickettsia phylogenetic groups. Comparative genomics revealed potential alternative resistance mechanisms, including additional amino acid variants that could hinder rifampin binding and genes that could facilitate rifampin detoxification through efflux pumps. Importantly, the evolutionary history of Rickettsia genomes indicates that the emergence of natural rifampin resistance is phylogenetically constrained within the genus, originating from ancient genetic features shared among a unique set of closely related Rickettsia species. Phylogenetic patterns appear to be the most reliable predictors of natural rifampin resistance, which is confined to a distinct monophyletic subclade known as Massiliae. The distinctive features of the RNA polymerase beta subunit in certain untested Rickettsia species suggest that R. raoultii, R. amblyommatis, R. gravesii, and R. kotlanii may also be naturally rifampin‐resistant species. Contrary to previous studies, the natural resistance of Rickettsia, a genus of intracellular bacteria, to the antibiotic rifampin is not solely due to the Leu‐973 residue in the RNA polymerase β subunit.