title: Contribution of the R8 substituent to the in vitro antibacterial potency of besifloxacin and comparator ophthalmic fluoroquinolones.
abstract: BACKGROUND
  Previous work has shown that besifloxacin, an 8-chloro-fluoroquinolone, has more potent activity against gram-positive pathogens than moxifloxacin and gatifloxacin, which carry an 8-methoxy group. This study was conducted to determine the contribution of the R7 and R8 substituent to fluoroquinolone antibacterial activity.
  
  
  METHODS
  Besifloxacin, moxifloxacin, gatifloxacin, their R8 structural analogs, and ciprofloxacin were tested against representative isolates of various gram-positive and gram-negative species and previously characterized fluoroquinolone-resistant mutants of Staphylococcus aureus. Minimum inhibitory and minimum bactericidal concentrations were determined according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Reserpine was used to determine the effect of efflux pumps on antibacterial activity.
  
  
  RESULTS
  In general, exchanging the R8 residue in besifloxacin slightly reduced the molecule's potency, while introducing an 8-chloro group in moxifloxacin increased its potency. A similar change in gatifloxacin had little to no effect. Substituting the R8 residues did not increase the susceptibility to the efflux pump inhibitor reserpine or result in a loss of bactericidal activity. In contrast, the positive control, ciprofloxacin, was shown to be a substrate for reserpine and lost bactericidal activity against some fluoroquinolone-resistant isolates of S. aureus.
  
  
  CONCLUSIONS
  The data presented here show that, depending on the R7 substituent, replacing an 8-methoxy group with an 8-chloro substituent can improve potency or can have little-to-no effect. These findings highlight the importance of the interplay between the R7 and R8 substituents in determining antibacterial potency.
authors: Department of Microbiology and Sterilization Sciences, Bausch + Lomb, Inc, Rochester, NY, USA.
authors: Wolfgang
authors: W
authors: Haas
authors: Christine M
authors: CM
authors: Sanfilippo
authors: Christine K
authors: CK
authors: Hesje
authors: Timothy W
authors: TW
authors: Morris
keywords: Staphylococcus aureus; besifloxacin; fluoroquinolone analogs; moxifloxacin; resistance
references: Nature. 2010 Aug 19;466(7309):935-40
references: 20686482
references: Am J Ophthalmol. 2011 Oct;152(4):567-574.e3
references: 21652021
references: Antimicrob Agents Chemother. 1993 Nov;37(11):2348-57
references: 8285618
references: Antimicrob Agents Chemother. 1998 Aug;42(8):1917-22
references: 9687384
references: Antimicrob Agents Chemother. 1998 Nov;42(11):2810-6
references: 9797208
references: J Antimicrob Chemother. 2010 Jul;65(7):1441-7
references: 20435780
references: Antimicrob Agents Chemother. 2001 Oct;45(10):2703-9
references: 11557458
references: Antimicrob Agents Chemother. 2009 Aug;53(8):3552-60
references: 19506065
references: Antimicrob Agents Chemother. 1996 Aug;40(8):1835-42
references: 8843290
references: Clin Ophthalmol. 2010 Apr 26;4:215-25
references: 20463787
references: J Chemother. 2011 Apr;23(2):80-6
references: 21571623
references: Drug Saf. 1999 Nov;21(5):407-21
references: 10554054
references: Surv Ophthalmol. 2005 Nov;50 Suppl 1:S55-63
references: 16257311
references: Antimicrob Agents Chemother. 1991 Aug;35(8):1647-50
references: 1656869
references: J Antimicrob Chemother. 1997 Apr;39(4):447-52
references: 9145816
references: Chemotherapy. 2011;57(5):363-71
references: 21996946
references: Antimicrob Agents Chemother. 1992 Oct;36(10):2108-17
references: 1332587
references: Antimicrob Agents Chemother. 2008 Feb;52(2):385-92
references: 17724149
references: J Antimicrob Chemother. 1997 Nov;40(5):639-51
references: 9421311
references: Paediatr Drugs. 2010 Apr 1;12(2):105-12
references: 20218747
references: Drugs. 1995;49 Suppl 2:222-5
references: 8549310
references: Adv Exp Med Biol. 1996;387:117-20
references: 8794202
references: Antimicrob Agents Chemother. 1994 Mar;38(3):594-601
references: 8203860
references: Clin Drug Investig. 2010;30(10):675-85
references: 20629472
references: Ophthalmology. 2009 Sep;116(9):1615-1623.e1
references: 19643483
references: Clin Infect Dis. 2001 Mar 15;32 Suppl 1:S16-22
references: 11249824