Effect of hydrophobicity and molecular mass on the accumulation of fluoroquinolones by Staphylococcus aureus

Ten novel fluoroquinolones, with similar chemical structures but differing antibacterial activities and hydrophobicities, were studied to evaluate the role of the physical properties of quinolones on their accumulation and antibacterial activity for Staphylococcus aureus. Six of the 10 agents and tosufloxacin were more active against quinolone-susceptible and -resistant S. aureus than the remaining four agents and several piperazinyl fluoroquinolones. Changes to the side chains of the pyrollidinyl substituent at the R7 position alone made little difference to the MICs. Comparison of MICs of agents that were structurally identical apart from the R1 substituents, confirmed that a t-butyl group confers enhanced activity against S. aureus over a cyclopropyl or ethyl group at this position. The steady-state concentrations (SSCs) of the 10 novel quinolones accumulated by wild-type S. aureus did not correlate with their MICs or chemical structures. There was no apparent relationship between logP of the quinolone and accumulation by S. aureus F77; however, accumulation was positively correlated with molecular mass for 9/10 agents (r = 0.745) confirming that high molecular mass is not a barrier to accumulation in S. aureus. For all 10 agents, the presence of carbonyl cyanide m-chlorophenylhydrazone (CCCP) increased the concentration of quinolone accumulated by SA-1199, suggesting that NorA was inhibited. The fold increase of the SSC in the presence of CCCP did not correlate with hydrophobicity, but the SSC of agents with either an ethyl or cyclopropyl group at R1 was increased two- to three-fold in the presence of CCCP, suggesting that affinity for the NorA efflux pump may be influenced by quinolone structure.