Staphylococcus aureus COL: An Atypical Model Strain of MRSA that Exhibits Slow Growth and Antibiotic Tolerance

Methicillin-resistant Staphylococcus aureus (MRSA) has been a pathogen of global concern since its emergence in the 1960s. As one of the first MRSA strains isolated, COL has become a common model strain of S. aureus . Here we report that COL is, in fact, an atypical strain of MRSA that exhibits slow growth (extended lag and doubling times) and multidrug tolerance, with minimum duration of killing (MDK) values 50-300% greater than other “model” strains of S. aureus. Genomic analysis identified three mutated genes in COL ( rpoB, gltX and prs ) with links to tolerance. Allele swapping experiments between COL and the closely related, non-tolerant Newman strain uncovered a complex interplay between these genes. However, Prs (phosphoribosyl pyrophosphate [PRPP] synthetase) accounted for most of the growth and tolerance phenotype of COL. ppGpp quantitation and transcriptomic comparison of COL and Newman revealed that COL does not exhibit slow growth as a result of partial stringent response activation, as previously proposed. Instead, COL exhibits downregulation of purine, histidine and tryptophan synthesis, three pathways that rely on PRPP. Overall, our findings indicate that COL is an atypical, antibiotic-tolerant strain of MRSA whose isolation predates the previous first report of tolerance among clinical isolates.