Therapeutic strategies that target bacterial virulence have received considerable attention. The type III secretion system (T3SS) is important for bacterial virulence and represents an attractive therapeutic target. A novel compound with a predicted T3SS inhibitory activity named CL-55 (N-(2,4-difluorophenyl)-4-(3-ethoxy-4-hydroxybenzyl)-5-oxo-5,6-dihydro-4H-[1,3,4]-thiadiazine-2-carboxamide) was previously characterized by low toxicity, high levels of solubility, stability and specific efficiency toward Chlamydia trachomatis in vitro and in vivo. In this study, we describe the action of CL-55 on Salmonella enterica serovar Typhimurium. We found that CL-55 does not affect Salmonella growth in vitro but suppresses Salmonella infection in vivo. The i.p. injection of CL-55 at a dose of 10 mg kg(-1) for 4 days significantly (500-fold) decreased the numbers of Salmonella in the spleen and peritoneal lavages and increased the survival rates in susceptible (BALB/c, I/St) and resistant (A/Sn) mice. Twelve days of therapy led to complete eradication of Salmonella in mice. Moreover, no pathogen was found 4-6 weeks post treatment. CL-55 was not carcinogenic or mutagenic, did not increase the level of chromosomal aberrations in bone marrow cells and had low toxicity in mice, rats and rabbits. Pharmacokinetic studies have shown that CL-55 rapidly disappears from systemic blood circulation and is distributed in the organs. Our data demonstrates that CL-55 affects S. enterica serovar Typhimurium in vivo and could be used as a substance in the design of antibacterial inhibitors for pharmaceutical intervention of bacterial virulence for infection.

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The derivatives of 4-quinolone-3-carboxylic acid containing one (norfloxacin, pefloxacin, ciprofloxacin, grepafloxacin), two (lomefloxacin, sparfloxacin), or three (fleroxacin, tosufloxacin) fluorine atoms are known as highly active antibacterial drugs. A necessary condition for the manifestation of high antibacterial activity in this series of compounds is that one of the fluorine atoms would occupy position 6 in the aromatic part of the quinolone nucleus [1]. Another important factor is the character of the substituent in position 7 of the quinolone nucleus. Using various combinations and variations of substituents in positions 6 and 7 of the quinolone molecule (as well as of those in positions 5 and 8) is still the main point in searching for new active compounds of this class.The bactericidal effect of 4-quinolones is commonly related to their ability to inhibit bacterial topoisomerase II (DNA-gyrase)-an enzyme that promotes the reaction of negative DNA supercoiling in bacteria. Two subunits A of this enzyme act by unwinding the DNA chain, cutting one strand of the double helix, forming one more turn of the supercoil, and resealing the cut strand. Two subunits B of DNA-gyrase implement the ATP hydrolysis and provide the energy necessary for the supercoiling process [2]. At present, it is believed that 4-quinolones inhibit the reaction of DNA supercoiling by binding to the gyrase-DNA complex at the instant of the double-strand DNA breaking. Indeed, mutation . However, the bactericidal effect of drugs belonging to the 4-quinolone group is not restricted to inhibiting DNA supercoiling. It was suggested that DNA breaks formed under the action of these compounds induce an SOS response in the damaged bacterial cell, the uncontrolled development of which can result in the loss of bacteria [2,4,5]. Over a few recent years, specialists of the Center for Drug Chemistry have synthesized a series of 6-nitro derivatives of 4-quinolone-3-carboxylic acid and determined special features of their antibacterial action in comparison to that of fluorine-containing quinolones [6][7][8]. The purpose of this work was to study the relationship between the ability of inhibiting DNA synthesis and the bactericidal action of fluoroand nitroquinolones with respect to the E. coli species with intact and mutant DNA-gyrase. We have also determined the ability of these compounds to act according to bactericidal mechanisms of the A and B types inherent in quinolones. EXPERIMENTAL PARTBacterial strains and their cultivation. The experiments were performed with the E. coli K12 strains KLl6thy (Hfr P. 0.45, thi 11 thy A24) and KL166 (Hfr P.0.45, thi 11 rel I thy A24 drm 13 gyr AI3) kindly provided by B. Bachmann (E. coli Genetic Stock Center) and the strain EC 1000/pJE43 (F, A(proB--lac) thi 1 supE44 strA/colEI ~d Ap-lac) [9] carrying a multicopy plasmid with the [3-galactosidase 0091-I 50X/99/3307-0343522.00 9

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