In Vitro and In Vivo Antimicrobial Activities of T-3811ME, a Novel Des-F(6)-Quinolone

Abstract

The in vitro and in vivo activities of T-3811ME, a novel des-F(6)-quinolone, were evaluated in comparison with those of some fluoroquinolones, including a newly developed one, trovafloxacin. T-3811, a free base of T-3811ME, showed a wide range of antimicrobial spectra, including activities against Chlamydia trachomatis, Mycoplasma pneumoniae, andMycobacterium tuberculosis. In particular, T-3811 exhibited potent activity against various gram-positive cocci, with MICs at which 90% of the isolates are inhibited (MIC90s) of 0.025 to 6.25 μg/ml. T-3811 was the most active agent against methicillin-resistant Staphylococcus aureus and streptococci, including penicillin-resistant Streptococcus pneumoniae (PRSP). T-3811 also showed potent activity against quinolone-resistant gram-positive cocci with GyrA and ParC (GrlA) mutations. The activity of T-3811 against members of the familyEnterobacteriaceae and nonfermentative gram-negative rods was comparable to that of trovafloxacin. In common with other fluoroquinolones, T-3811 was highly active against Haemophilus influenzae, Moraxella catarrhalis, andLegionella sp., with MIC90s of 0.0125 to 0.1 μg/ml. T-3811 showed a potent activity against anaerobic bacteria, such as Bacteroides fragilis and Clostridium difficile. T-3811 was the most active agent against C. trachomatis (MIC, 0.008 μg/ml) and M. pneumoniae(MIC90, 0.0313 μg/ml). The activity of T-3811 againstM. tuberculosis (MIC90, 0.0625 μg/ml) was potent and superior to that of trovafloxacin. In experimental systemic infection with a GrlA mutant of S. aureus and experimental pneumonia with PRSP in mice, T-3811ME showed excellent therapeutic efficacy in oral and subcutaneous administrations.

Clinical studies of garenoxacin

“…1). As with other fluoroquinolones, GRN acts on DNA gyrase and DNA topoisomerase IV to inhibit the transcription and replication of DNA [6]. GRN shows highly potent activity against Staphylococcus aureus, S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, bacteria that often cause respiratory and otorhinolaryngological infections, and is also highly potent against atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniae [7][8][9][10].…”

Prospects for development of new antimycobacterial drugs

“…16,18,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Fluoroquinolones exhibit fairly potent anti-MTB, anti-M. kansasii, and anti-M. fortuitum activities, 16,20,26,27 and the in-vitro anti-MTB activities of new quinolones, as determined by their MICs, are in the order STFX Լ GFLX Լ MXFX Լ SPFX Ͼ LVFX м CPFX Ͼ OFLX. 16,[20][21][22][23]27,29,32,39 Newly synthesized quinolones, such as WQ-3034 and HSR-903, had activity against MTB comparable to that of LVFX, 23,39 and newly Alangaden (1995), Kawahara (1994), , Skinner (1995) Ji ( , 1998, , Herbert (1996), , Sbarbaro (1996), Yajko (1996), Tomioka (1996 Tomioka (1990, Saito (1990, Ji ( , 1998, 33,35 Although fluoroquinolones also exhibit efficacy against MAC in combination with EB, CFZ, AMK, RFP, and rifabutin (RBT), their anti-MAC activities are relatively weak.…”

Quinolone Antibiotics: The Development of Moxifloxacin

“…They provide additional information on the structure-activity relationships of DNA gyrase inhibitors [282]. Of the 6-desfluoroquinolones, garenoxacin 90 [4], which has an aryl side chain in the 7-position, has been most widely investigated: it is highly active, well-tolerated and, compared to the fluoroquinolones, is less chondrotoxic in juvenile dogs and rats [10,66,267,283]. [284,285], and premafloxacin 92 with a 3-(1-methylaminoethyl)-1-pyrrolidinyl radical in the 7-position and an 8-methoxy group [286,287].…”

“…In recent years, several promising quinolones have, however, been described in which the fluorine atom has been removed from the 6-position. One example of such compounds, which are referred to as 6-desfluoroquinolones, is garenoxacin (T 3811, BMS 384 756) 90 [4], which was discovered by Toyama and is presently being developed in cooperation with Schering-Plough. Quinolones interfere with the replication mechanism of bacteria by inhibiting essential enzymes such as DNA gyrase (topoisomerase II) and topoisomerase IV, thereby preventing supercoiling and decatenation of the bacterial DNA and the replication of the latter [5][6][7][8][9][10][11][12].…”