Hydrophilicity of quinolones is not an exclusive factor for decreased activity in efflux-mediated resistant mutants of Staphylococcus aureus

Abstract

The elevated expression of the norA gene is responsible for efflux-mediated resistance to quinolones in Staphylococcus aureus (E.Y.W. Ng, M. Trucksis, and D.C. Hooper, Antimicrob. Agents Chemother. 38:1345-1355, 1994). For S. aureus transformed with a plasmid containing the cloned norA gene, SA113(pTUS20) (H. Yoshida, M. Bogaki, S. Nakamura, K. Ubukata, and M. Konno, J. Bacteriol. 172:6942-6949, 1990), and an overexpressed mutant, SA-1199B (G.W. Kaatz, S.M. Seo, and C.A. Ruble, J. Infect. Dis. 163:1080-1086, 1991), the MICs of norfloxacin increased 16 and 64 times compared with its MICs for the recipient and wild-type strains, SA113 and SA-1199, respectively. MICs of CS-940, however, increased only two and eight times, even though these two fluoroquinolones are similarly hydrophilic (apparent logPs of approximately -1). No good correlation was found, among 15 developed and developing quinolones, between the increment ratio in MICs and hydrophobicity (r = 0.61). Analysis of the quantitative structure-activity relationship among 40 fluoroquinolones revealed that the MIC increment ratio was significantly correlated with the bulkiness of the C-7 substituent and bulkiness and hydrophobicity of the C-8 substituent of fluoroquinolones (r = 0.87) and not with its molecular hydrophobicity (r = 0.47). Cellular accumulation of norfloxacin in SA-1199B was significantly lower than that in SA-1199, and it was increased by addition of carbonyl cyanide m-chlorophenyl hydrazone. On the other hand, accumulations of CS-940 in these strains were nearly identical, and they were not affected by addition of the protonophore.

Contribution of the R8 substituent to the in vitro antibacterial potency of besifloxacin and comparator ophthalmic fluoroquinolones

“…Changing the 8-chloro to an 8-methoxy resulted in 11 (20.7%) additional strains that exhibited a reserpine-induced twofold decrease in MIC values, a change that could be due to natural fluctuations or due to an increased ability of NorA to export BMO when compared to besifloxacin. The latter hypothesis is consistent with work by Takenouchi et al, who proposed a correlation between the activity of efflux pumps and the bulkiness of the R7 substituent and the bulkiness and hydrophobicity of the R8 substituent 23. However, even if replacement of the 8-chloro with an 8-methoxy group made BMO a better substrate for NorA, the effect is rather subtle and probably not biologically significant.…”

Activity of finafloxacin, a novel fluoroquinolone with increased activity at acid pH, towards extracellular and intracellular Staphylococcus aureus, Listeria monocytogenes and Legionella pneumophila

“…Indeed, examination of the biophysical properties of finafloxacin contradicts the generally accepted rule that it is the hydrophobic character of a fluoroquinolone that allows it to escape recognition and efflux by NorA and related transporters [35]. The data rather suggest that the bulkiness of the substituents at C-7 and C-8 is much more critical [36].…”

Modulation of drug resistance in staphylococcus aureus by a kaempferol glycoside from herissantia tiubae (malvaceae)

“…Among the fluorquinolones used here, ofloxacin is the most hydrophobic (Kaatz et al, 1993;Takenouchi et al, 1996), and as pointed out by Gibbons et al (2003), hydrophobicity is a factor that may reduce recognition and transport by an efflux pump (see also : Piddock et al, 2001).…”