Showing papers on "Quinolone published in 2001"
TL;DR: A number of 7-substituted quinolone derivatives were synthesized and evaluated for antibacterial and cytotoxic activities and preliminary results indicated that most compounds tested demonstrated better activity against methicillin-resistant Staphylococcus aureus than norfloxacin.
Abstract: A number of 7-substituted quinolone derivatives were synthesized and evaluated for antibacterial and cytotoxic activities. Preliminary results indicated that most compounds tested in this study demonstrated better activity against methicillin-resistant Staphylococcus aureus than norfloxacin. Among them, 1-(4-amino-2-fluorophenyl)-6-fluoro-1,4-dihydro-7-[4-[2-(4-methoxyphenyl)-2-hydroxyiminoethyl]-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid (11d) and its ketone precursor 10d exhibited significant activities against Klebsiella pneumoniae, methicillin-resistant S. aureus, erythromycin- and ampicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis. Due to strong cytotoxicities of 11d (a mean log GI(50) of -5.40), compound 10d, with good antibacterial activities and low cytotoxicities (a mean log GI(50) of -4.67), is a more potential drug candidate.
501 citations
TL;DR: This review will discuss the mechanistic basis for drug efficacy and interactions between these compounds and their topoisomerase targets, as well as cultured mammalian cells and in vivo tumor models.
Abstract: Quinolones are a very important family of antibacterial agents that are widely prescribed for the treatment of infections in humans. Although the founding members of this drug class had little clinical impact, successive generations include the most active and broad spectrum oral antibacterials currently in use. In contrast to most other anti-infective drugs, quinolones do not kill bacteria by inhibiting a critical cellular process. Rather, they corrupt the activities of two essential enzymes, DNA gyrase and topoisomerase IV, and induce them to kill cells by generating high levels of double-stranded DNA breaks. A second unique aspect of quinolones is their differential ability to target these two enzymes in different bacteria. Depending upon the bacterial species and quinolone employed, either DNA gyrase or topoisomerase IV serves as the primary cytotoxic target of drug action. While this unusual feature initially stymied development of quinolones with high activity against Gram-positive bacteria, it ultimately opened new vistas for the clinical use of this drug class. In addition to the antibacterial quinolones, specific members of this drug family display high activity against eukaryotic type II topoisomerases, as well as cultured mammalian cells and in vivo tumor models. These antineoplastic quinolones represent a potentially important source of new anticancer agents and provide an opportunity to examine drug mechanism across divergent species. Because of the clinical importance of quinolones, this review will discuss the mechanistic basis for drug efficacy and interactions between these compounds and their topoisomerase targets.
174 citations
TL;DR: It is demonstrated that the double-mutant enzyme-DNA complex has a lower affinity for ciprofloxacin than the wild-type complex, based on the pattern of resistance to a series of quinolones.
Abstract: DNA gyrase is a target of quinolone antibacterial agents, but the molecular details of the quinolone-gyrase interaction are not clear. Quinolone resistance mutations frequently occur at residues Ser(83) and Asp(87) of the gyrase A subunit, suggesting that these residues are involved in drug binding. Single and double alanine substitutions were created at these positions (Ala(83), Ala(87), and Ala(83) Ala(87)), and the mutant proteins were assessed for DNA supercoiling, DNA cleavage, and resistance to a number of quinolone drugs. The Ala(83) mutant was fully active in supercoiling, whereas the Ala(87) and the double mutant were 2.5- and 4- to 5-fold less active, respectively; this loss in activity may be partly due to an increased affinity of these mutant proteins for DNA. Supercoiling inhibition and cleavage assays revealed that the double mutant has a high level of resistance to certain quinolones while the mutants with single alanine substitutions show low-level resistance. Using a drug-binding assay we demonstrated that the double-mutant enzyme-DNA complex has a lower affinity for ciprofloxacin than the wild-type complex. Based on the pattern of resistance to a series of quinolones, an interaction between the C-8 group of the quinolone and the double-mutant gyrase in the region of residues 83 and 87 is proposed.
160 citations
TL;DR: In this paper, the authors studied the relationship between Escherichia coli resistance and quinolone use and showed that the number of resistant strains in these isolates are the same as those in resistant strains found in humans.
Abstract: Escherichia coli is an important pathogen of animals and humans that causes great financial cost in food production by causing disease in food animals. The quinolones are a class of synthetic antimicrobial agents with excellent activity against Escherichia coli and other Gram-negative bacteria used in human and veterinary medicine. Different quinolones are used to treat various conditions in animals in different parts of the world. All members of this class of drug have the same mode of action: inhibition of topoisomerase enzymes, DNA Gyrase and Topoisomerase IV. Escherichia coli can become resistant to quinolones by altering the target enzymes, reducing permeability of the cell to inhibit their entry, or by actively pumping the drug out of the cell. All these resistance mechanisms can play a role in high-level fluoroquinolone resistance, however target site mutations appear to be most important. As all quinolones act in the same way resistance to one member of the class will also confer decreased susceptibility to all members of the family. Quinolone resistant Escherichia coli in animals have increased in numbers after quinolone introduction in a number of different case studies. The resistance mechanisms in these isolates are the same as those in resistant strains found in humans. Care needs to be taken to ensure that quinolones are used sparingly and appropriately as highly resistant strains of Escherichia coli can be selected and may pass into the food chain. As these drugs are of major therapeutic importance in human medicine, this is a public health concern. More information as to the numbers of quinolone resistant Escherichia coli and the relationship between resistance and quinolone use is needed to allow us to make better informed decisions about when and when not to use quinolones in the treatment of animals.
125 citations
TL;DR: In the presence of ATP, or the non-hydrolysable analogue 5′-adenylyl β,γ-imidodiphosphate, microcin B17 stabilises a gyrase-dependent DNA cleavage complex in a manner reminiscent of quinolones, Ca2+, or the bacterial toxin CcdB as mentioned in this paper.
122 citations
TL;DR: In three Escherichia coli mutants, a change (Ala-51 to Val) in the gyrase A protein outside the standard quinolone resistance-determining region (QRDR) lowered the level of quinoline susceptibility more than changes at amino acids 67, 82, 84, and 106 did.
Abstract: In three Escherichia coli mutants, a change (Ala-51 to Val) in the gyrase A protein outside the standard quinolone resistance-determining region (QRDR) lowered the level of quinolone susceptibility more than changes at amino acids 67, 82, 84, and 106 did. Revision of the QRDR to include amino acid 51 is indicated.
117 citations
TL;DR: In this article, B. anthracis Sterne was grown from a live veterinary vaccine and used it to test for the development of resistance after 21 sequential subcultures in sub-inhibitory concentrations of doxycycline and three quinolones (ciprofloxacin, alatrofloxacan, and gatifloxacan).
99 citations
01 Jan 2001
TL;DR: Bacillus anthracis Sterne was grown from a live veterinary vaccine and used to test for the development of resistance after 21 sequential subcultures in sub-inhibitory concentrations of doxycycline and three quinolones and each isolate was cross-tested for resistance using the other drugs.
Abstract: Bacillus anthracis is a potential biological warfare agent. Its ability to develop resistance to antimicrobial agents currently recommended for the treatment of anthrax infection is a major concern. B. anthracis Sterne was grown from a live veterinary vaccine and used it to test for the development of resistance after 21 sequential subcultures in sub-inhibitory concentrations of doxycycline and three quinolones (ciprofloxacin, alatrofloxacin and gatifloxacin) and 15 sequential subcultures in sub-inhibitory concentrations of three macrolides (erythromycin, azithromycin and clarithromycin). After 21 subcultures the minimal inhibitory concentrations (MICs) increased from 0.1 to 1.6 mg/l for ciprofloxacin, from 1.6 to 12.5 mg/l for alatrofloxacin, from 0.025 to 1.6 mg/l for gatifloxacin and from 0.025 to 0.1 mg/l for doxycycline. After 15 passages of sequential subculturing with macrolides, the MICs increased from 12.5 to 12.5 or 50.0 mg/l for azithromycin, from 0.2 to 1.6 or 0.4 mg/l for clarithromycin and from 6.25 to 6.25 or 50 mg/l for erythromycin. After sequential passages with a single quinolone or doxycycline, each isolate was cross-tested for resistance using the other drugs. All isolates selected for resistance to one quinolone were also resistant to the other two quinolones, but not to doxycycline. The doxycycline-resistant isolate was not resistant to any quinolone. © 2001 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved.
92 citations
TL;DR: Three mechanisms of resistance against quinolones are mutations of topoisomerases, decreased membrane permeability, and active drug efflux, although these mechanisms occur singly, several resistance factors are often required to produce clinically applicable increases in minimum inhibitory concentrations.
Abstract: A topoisomerase was identified as the bacterial target site for quinolone action in the late 1970s. Since that time, further study identified two bacterial topoisomerases, DNA gyrase and topoisomerase IV, as sites of antibacterial activity. DNA gyrase appears to be the primary quinolone target for gram-negative bacteria. Topoisomerase IV appears to be the preferential target in gram-positive organisms, but this varies with the drug. Three mechanisms of resistance against quinolones are mutations of topoisomerases, decreased membrane permeability, and active drug efflux. Although these mechanisms occur singly, several resistance factors are often required to produce clinically applicable increases in minimum inhibitory concentrations. Appropriate drug selection and dosage and prudent human and veterinary interventions are important factors in controlling the emergence of resistance.
83 citations
TL;DR: Findings indicate that resistance to MXF in a majority of cases may be due to amino acid substitution in thegyrA gene, which is the etiological agent of antibiotic-associated colitis and the most common cause of hospital-acquired infectious diarrhea.
Abstract: Clostridium difficile is the etiological agent of antibiotic-associated colitis and the most common cause of hospital-acquired infectious diarrhea. Fluoroquinolones such as ciprofloxacin are associated with lower risks of C. difficile-associated diarrhea. In this study, we have analyzed 72 C. difficile isolates obtained from patients with different clinical courses of disease, such as toxic megacolon and relapses; the hospital environment; public places; and horses. They were investigated for their susceptibilities to moxifloxacin (MXF), metronidazole (MEO), and vancomycin (VAN). Mutants highly resistant to fluoroquinolones were selected in vitro by stepwise exposure to increasing concentrations of MXF. The resulting mutants were analyzed for the presence of mutations in the quinolone resistance-determining regions of DNA gyrase (gyrA), the production of toxins A and B, and the epidemiological relationship of these isolates. These factors were also investigated using PCR-based methods. All strains tested were susceptible to MEO and VAN. Twenty-six percent of the clinical isolates (19 of 72) were highly resistant to MXF (MIC ≥ 16 μg/ml). Fourteen of these 19 strains contained nucleotide changes resulting in amino acid substitutions at position 83 in the gyrA protein. Resistant strains selected in vitro did not contain mutations at that position. These findings indicate that resistance to MXF in a majority of cases may be due to amino acid substitution in the gyrA gene.
79 citations
TL;DR: The effect of several pyridoquinoline derivatives that restore a noticeable fluoroquinolone accumulation to resistant strains that overexpress the MarA activator is reported, indicating that the most efficient derivatives tested probably inhibit the resistance process by acting as substrate competitors on the pump extruding intracellular norfloxacin.
Abstract: Enterobacter aerogenes, one of the most frequently isolated nosocomial pathogens in France, is exhibiting increasing multidrug resistance mechanisms associated with a change in membrane permeability. For drugs of the quinolone family, mutations in the target and active efflux play a prominent role in the resistance. We report here the effect of several pyridoquinoline derivatives that restore a noticeable fluoroquinolone accumulation to resistant strains that overexpress the MarA activator. Studies of the energy-dependent quinolone efflux indicate that the most efficient derivatives tested probably inhibit the resistance process by acting as substrate competitors on the pump extruding intracellular norfloxacin.
TL;DR: It is hypothesized that the 8-methoxy group of gatifloxacin increases the level of target inhibition, especially against DNA gyrase, so that it is nearly the same as that for topoisomerase IV inhibition in the bacterial cell, leading to potent antibacterial activity and a low level of resistance selectivity.
Abstract: Streptococcus pneumoniae is one of the most important pathogens and is responsible for community-acquired pneumonia, acute otitis media, and meningitis. Recently, the worldwide prevalence of penicillin-resistant S. pneumoniae has become a serious problem in clinical settings. Therefore, antibiotics that possess potent activity against penicillin-resistant as well as penicillin-susceptible S. pneumoniae are urgently needed.
Some of the recently developed fluoroquinolones have improved activities against respiratory pathogens, including S. pneumoniae, and are expected to be useful as chemotherapeutic agents for the treatment of patients infected with such pathogens (1, 6, 11, 12, 20, 21, 33, 34). Recent clinical assessments of the susceptibility of S. pneumoniae to antibacterial agents have indicated that most clinical isolates continue to retain their quinolone susceptibility (9, 15, 31). Nevertheless, an outbreak of quinolone-resistant S. pneumoniae has recently been reported (K. Weiss, C. Restieri, M. Laverdiere, R. J. Davidson, A. McGeer, J. De Azavedo, and D. E. Low, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother., Abstr. 824, p. 110, 1999). In conjunction with the increasing clinical use of fluoroquinolone for the treatment of respiratory infections, the increasing prevalence of quinolone resistance is anticipated in S. pneumoniae, as recently occurred in methicillin-resistant Staphylococcus aureus. Therefore, it is important to try to prevent the acquisition of quinolone resistance in S. pneumoniae.
In number of studies on the in vitro selection of quinolone-resistant strains of S. pneumoniae, investigators have reported observing different frequencies of resistance selectivity among fluoroquinolones (4, 8). It has been suggested that gatifloxacin and clinafloxacin possess potent antipneumococcal activities and select mutant strains less frequently than other fluoroquinolones because of their inhibition of DNA gyrase and topoisomerase IV (TopoIV), which occur at nearly the same levels in bacterial cells (dual-targeting property) (8, 23). On the other hand, it has been reported that the ease of resistance selectivity in S. pneumoniae correlated with the susceptibilities of the agents to the bacterial NorA-type efflux system (4).
Gatifloxacin harbors a characteristic methoxy group at the 8 position of the quinolone ring. The contributions of the methoxy groups of certain fluoroquinolones, including gatifloxacin, to antibacterial activity and/or resistance selectivity have been investigated in some bacteria. The methoxy group has been shown to correlate with the prevention of emergence of the mutant strains and/or potent in vitro activity against Escherichia coli (17, 38), S. aureus (13, 14, 39), and mycobacteria (5, 29, 37).
In the study described in this report, we investigated the contribution of the 8-methoxy group of gatifloxacin to resistance selectivity, target preference, and the antibacterial activity against S. pneumoniae.
(This study was presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, 26 to 29 September 1999.)
TL;DR: Pneumoniae gyrase gyrA and topoisomerase IV parC genes encoding respective Ser81Phe and Ser79Phe mutations provide strong support for a model in which quinolones kill S. pneumoniae by acting not as enzyme inhibitors but as cellular poisons, with sparfloxacin killing preferentially through gyrases and ciprofloxACin through topoisomersase IV.
Abstract: Mutations in DNA gyrase and/or topoisomerase IV genes are frequently encountered in quinolone-resistant mutants of Streptococcus pneumoniae. To investigate the mechanism of their effects at the molecular and cellular levels, we have used an Escherichia coli system to overexpress S. pneumoniae gyrase gyrA and topoisomerase IV parC genes encoding respective Ser81Phe and Ser79Phe mutations, two changes widely associated with quinolone resistance. Nickel chelate chromatography yielded highly purified mutant His-tagged proteins that, in the presence of the corresponding GyrB and ParE subunits, reconstituted gyrase and topoisomerase IV complexes with wild-type specific activities. In enzyme inhibition or DNA cleavage assays, these mutant enzyme complexes were at least 8- to 16-fold less responsive to both sparfloxacin and ciprofloxacin. The ciprofloxacin-resistant (Cip(r)) phenotype was silent in a sparfloxacin-resistant (Spx(r)) S. pneumoniae gyrA (Ser81Phe) strain expressing a demonstrably wild-type topoisomerase IV, whereas Spx(r) was silent in a Cip(r) parC (Ser79Phe) strain. These epistatic effects provide strong support for a model in which quinolones kill S. pneumoniae by acting not as enzyme inhibitors but as cellular poisons, with sparfloxacin killing preferentially through gyrase and ciprofloxacin through topoisomerase IV. By immunoblotting using subunit-specific antisera, intracellular GyrA/GyrB levels were a modest threefold higher than those of ParC/ParE, most likely insufficient to allow selective drug action by counterbalancing the 20- to 40-fold preference for cleavable-complex formation through topoisomerase IV observed in vitro. To reconcile these results, we suggest that drug-dependent differences in the efficiency by which ternary complexes are formed, processed, or repaired in S. pneumoniae may be key factors determining the killing pathway.
TL;DR: This is the first report describing a fluoroquinolone antimicrobial agent whose primary target is suggested to be DNA gyrase in S. aureus.
TL;DR: Mutational events in the QRDR of gyrA seem to contribute to quinolone resistance in B. fragilis species, which can be readily selected in vivo.
Abstract: Mutations in the gyrA gene contribute considerably to quinolone resistance in Escherichia coli. Mechanisms for quinolone resistance in anaerobic bacteria are less well studied. The Bacteroides fragilis group are the anaerobic organisms most frequently isolated from patients with bacteremia and intraabdominal infections. Forty-four clinafloxacin-resistant and-susceptible fecal and clinical isolates of the B. fragilis group (eight Bacteroides fragilis, three Bacteroides ovatus, five Bacteroides thetaiotaomicron, six Bacteroides uniformis, and 22 Bacteroides vulgatus) and six ATCC strains of the B. fragilis group were analyzed as follows: (i) determination of susceptibility to ciprofloxacin, levofloxacin, moxifloxacin, and clinafloxacin by the agar dilution method and (ii) sequencing of the gyrA quinolone resistance-determining region (QRDR) located between amino acid residues equivalent to Ala-67 through Gln-106 in E. coli. Amino acid substitutions were found at hotspots at positions 82 (n = 15) and 86 (n = 8). Strains with Ser82Leu substitutions (n = 13) were highly resistant to all quinolones tested. Mutations in other positions of gyrA were also frequently found in quinolone-resistant and -susceptible isolates. Eight clinical strains that lacked mutations in their QRDR were susceptible to at least two of the quinolones tested. Although newer quinolones have good antimicrobial activity against the B. fragilis group, quinolone resistance in B. fragilis strains can be readily selected in vivo. Mutational events in the QRDR of gyrA seem to contribute to quinolone resistance in Bacteroides species.
01 Jan 2001
TL;DR: This study of recent European S. pneumoniae isolates can be used to recognize any changes in susceptibility patterns and resistance mechanisms that may occur in the future.
Abstract: Streptococcus pneumoniae isolates (n=1191) were collected during a 1997–1999 European surveillance study. In addition to susceptibility data, a molecular epidemiological survey of their mechanisms of resistance to macrolides, tetracyclines, and quinolones was provided. Of the isolates tested, 72.6% were penicillin-susceptible, 19.9% penicillin-intermediate and 7.5% penicillin-resistant. There was an obvious relationship between resistance to penicillin and resistance to erythromycin (19% of all isolates), clindamycin (14%) and tetracycline (23%). Only one isolate was resistant to levofloxacin. Seventy-three percent of the European S. pneumoniae isolates resistant to erythromycin (n= 229) carried the erm(B) gene, while the remaining 27% possessed the mef(A) gene. No mutations were detected in 23S rRNA or in ribosomal proteins L4 and L22. All tetracycline-resistant isolates (n=277) carried the tet(M) gene; none carried the tet(O) gene. Classical mutations in gyrA (Ser 81-Phe or Tyr) and parC (Ser 79-Phe and Asp 83-Asn) and efflux contributed to the decreased quinolone susceptibility. This study of recent European S. pneumoniae isolates can be used to recognize any changes in susceptibility patterns and resistance mechanisms that may occur in the future. © 2001 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved.
TL;DR: The newly developed 8-methoxy, non-fluorinated quinolones (NFQs) were studied to elucidate their enzyme inhibitory activity against wild-type and mutant GyrA (Ser-83-->Trp) forms of Escherichia coli DNA gyrase.
Abstract: The newly developed 8-methoxy, non-fluorinated quinolones (NFQs) were studied to elucidate their enzyme inhibitory activity against wild-type and mutant GyrA (Ser-83-->Trp) forms of Escherichia coli DNA gyrase. Using a DNA supercoiling inhibition assay, the NFQs were found to inhibit 50% (IC50) of the E. coli DNA gyrase activity in the 1.6-3.2 mg/L concentration range and were comparable to ciprofloxacin. However, against the GyrA (Ser-83-->Trp) mutant, the NFQs were approximately 16-fold more potent than ciprofloxacin. Antibacterial potency of the NFQs was investigated using clinical isolates of E. coli and penicillin-resistant Streptococcus pneumoniae (PRSP), including strains with reduced susceptibility to quinolones. Against 20 uncharacterized clinical isolates of E. coli, the MIC90s of the NFQs were in the 0.125-0.25 mg/L range while those of ciprofloxacin, trovafloxacin, gatifloxacin and clinafloxacin were in the 0.016-0.125 mg/L range. Against clinical isolates with characterized mutations in gyrA and parC, PGE9262932, an NFQ, was two- to eight-fold more potent than ciprofloxacin. Against 23 clinical isolates of PRSP, the NFQs (MIC90 0.031-0.125 mg/L) were more potent than ciprofloxacin, trovafloxacin, and gatifloxacin (MIC90 0.25-2.0 mg/L), and at least as potent as clinafloxacin (MIC90 0.125 mg/L). Against S. pneumoniae strains with gyrA and parC mutations, the NFQs (MIC 0.125-1.0 mg/L) were more potent than ciprofloxacin, trovafloxacin and gatifloxacin (MIC 4-32 mg/L), and comparable to clinafloxacin (MIC 0.5-1 mg/L).
TL;DR: A molecular epidemiological survey of the mechanisms of resistance to macrolides, tetracyclines, and quinolones was provided in this paper, showing an obvious relationship between resistance to penicillin and resistance to erythromycin.
TL;DR: Investigations aiming at understanding the molecular mechanisms of quinolone action and resistance in more detail should provide a basis for a rational design of more potent derivatives of these highly valuable "magic bullets".
Abstract: The quinolone class of inhibitors of bacterial type II topoisomerases has gained major clinical importance during the last years due to improvements in both pharmacokinetic and pharmacodynamic properties. These include favorable bioavailability allowing oral administration, good tolerability, high tissue concentrations as well as superior bactericidal activity against a broad spectrum of clinically relevant pathogens, like enterobacteria, Pseudomonas aeruginoso, Staphylococcus aureus, and Streptococcus pneumoniae. In addition, no enzymatic mechanism of drug inactivation exists in bacteria and no indications for transfer of clinically relevant resistance exist. Nevertheless, resistance is being increasingly reported, even for naturally highly susceptible species like Escherichia coli. The underlying mechanisms of resistance include alterations in both bacterial targets, DNA gyrase and topoisomerase IV, often combined with mutations affecting drug accumulation, e.g., by increased drug efflux, reduced drug influx, or both. Investigations aiming at understanding the molecular mechanisms of quinolone action and resistance in more detail should provide a basis for a rational design of more potent derivatives. In addition, a prudent use of these highly valuable "magic bullets" is necessary to preserve their potential for the future.
TL;DR: It is suggested that DNA gyrase is the main intracellular target of MccB17, and steady-state parameters are used to describe the induction of the cleavable complex by MCCB17 analogs containing modified bisheterocyclic sites, and the relative potency of these analogs corresponds to the capacity of the compounds to prevent growth of sensitive cells.
Abstract: Microcin B17 (MccB17) is a 3.1-kDa Escherichia coli antibiotic that contains thiazole and oxazole heterocycles in a peptide backbone. MccB17 inhibits its cellular target, DNA gyrase, by trapping the enzyme in a complex that is covalently bound to double-strand cleaved DNA, in a manner similar to the well-known quinolone drugs. The identification of gyrase as the target of MccB17 provides an opportunity to analyze the relationship between the structure of this unusual antibiotic and its activity. In this report, steady-state parameters are used to describe the induction of the cleavable complex by MccB17 analogs containing modified bisheterocyclic sites. The relative potency of these analogs corresponds to the capacity of the compounds to prevent growth of sensitive cells. In contrast to previously reported experiments, inhibition of DNA gyrase supercoiling activity by wild-type MccB17 also was observed. These results suggest that DNA gyrase is the main intracellular target of MccB17. This study probes the structure-function relationship of a new class of gyrase inhibitors and demonstrates that these techniques could be used to analyze compounds in the search for clinically useful antibiotics that block DNA gyrase.
Patent•
29 Nov 2001TL;DR: In this article, the quinolone derivatives possess antibacterial activity, and are effective against a number of human and veterinary pathogens in the treatment of bacterial diseases, such as salmonella infection.
Abstract: Substituted quinolone derivatives in which an oxazolidinone, isoxazolinone, or isoxazoline is covalently bonded to a quinolone, methods of using the quinolone derivatives, and pharmaceutical compositions containing the quinolone derivatives are disclosed. Methods of synthesizing these substituted quinolone derivatives are also disclosed, and in particular a method of manufacturing a 7-(2-oxo-1,3-oxazolidin-3-yl)aryl-3-quinolinecarboxylic acid by condensing a 4-(2-oxo-1,3-oxazolidin-5-yl)aryl boronic acid with a 7-halo-quinolone derivative. The quinolone derivatives possess antibacterial activity, and are effective against a number of human and veterinary pathogens in the treatment of bacterial diseases.
TL;DR: The C-8 methoxy quinolone moxifloxacin is highly bactericidal against wild-type and first-step gyrase- and topoisomerase IV-resistant mutants, and the hypothesis that the C- 8 methoxy group may lower the propensity for resistance development compared with quInolones possessing different substituents at theC-8 position was proposed.
Abstract: The C-8 methoxy quinolone moxifloxacin is highly bactericidal against wild-type and first-step gyrase- and topoisomerase IV-resistant mutants. This finding led to the hypothesis that the C-8 methoxy group may lower the propensity for resistance development compared with quinolones possessing different substituents at the C-8 position. Therefore, resistance development of the C-8 methoxy quinolone moxifloxacin was compared with that of its structural analogue BAY y 3118 (chlorine moiety at the C-8 position), with Staphylococcus aureus used as the test organism. The spontaneous emergence of resistance was quantified by counting the number of colonies growing on drug-free medium compared with moxifloxacin- or BAY y 3118-containing media. The multistep emergence of quinolone resistance was encountered by growing S. aureus over 8 passages in drug-containing medium. Human serum concentrations were simulated in an in vitro model over 84 h (dosing every 24 h), and total and resistant S. aureus were quantified. Spontaneous mutation frequencies of 6 X 10 11 for moxifloxacin and 4 X 10 7 for BAY y 3118 were observed. Multistep resistance to moxifloxacin developed slowly (2-fold rise) but rapidly against BAY y 3118 (>16-fold rise). No resistance against moxifloxacin developed in this model, whereas resistance to BAY y 3118 began to develop after 4 h. Thus, as the C-8 moiety was the only difference, the 8-methoxy group on moxifloxacin appeared to significantly lower the propensity for quinolone resistance development.
TL;DR: The recent discovery of non-fluoroquinolones and 2-pyridone antibacterials represents yet additional progress in the search for novel DNA gyrase inhibitors.
Abstract: The therapeutic use of DNA gyrase inhibitors, mainly quinolone antibacterials, has proven to be a tremendous success story in the treatment of bacterial infections. The rapid changes in quinolone research and development in recent years have produced several new quinolones: moxifloxacin, gatifloxacin, gemifloxacin and des-6-fluoroquinolone antibacterials. These newly developed compounds are equal or superior to existing ones in their potency, spectrum of activity, pharmacodynamics/pharmacokinetics and safety profiles. The recent discovery of non-fluoroquinolones and 2-pyridone antibacterials represents yet additional progress in the search for novel DNA gyrase inhibitors. Although these two classes of compounds are either in the discovery or early development phase, they extend the possibilities of establishing new structure-activity relationships and new chemotypes for DNA gyrase inhibition.
TL;DR: The findings support the occurrence of interspecies recombination of type II topoisomerase genes; however, its contribution to the emergence of quinolone resistance among pneumococci appears to have been minimal.
Abstract: Analysis of 71 ciprofloxacin-resistant (MIC ≥ 4 μg/ml) Streptococcus pneumoniae clinical isolates revealed only 1 for which the quinolone resistance-determining regions of the parC, parE, and gyrB genes were genetically related to those of viridans group streptococci Our findings support the occurrence of interspecies recombination of type II topoisomerase genes; however, its contribution to the emergence of quinolone resistance among pneumococci appears to have been minimal
TL;DR: In this paper, the B subunit of DNA gyrase (GyrB) was found to be more sensitive to quinolone drugs with respect to bacteriostatic and lethal action.
TL;DR: A novel des-F(6)-quinolone demonstrated greater Gram-positive antibacterial activity and similar inhibition of targets compared with other fluoroquinolones, and more favourable selectivity compared with the other BMS-284756 analogues.
Abstract: Analogues of BMS-284756, a novel des-F(6)-quinolone, were synthesized and evaluated in order to determine the effects of modification of substituents on in vitro target inhibition. BMS-340281 (stereoisomer of BMS-284756), BMS-340280 (C-6 fluorinated analogue of BMS-284756), BMS-340278 (C-8-H derivative), BMS-433366 (C-8 methoxy analogue) and fluoroquinolone comparators were evaluated for antibacterial activity. The MICs of BMS-284756 were generally found to be within two-fold of the MICs of BMS-284756 analogues against a panel of Gram-positive and -negative organisms. BMS-284756 had MICs of 0.03-0.125 mg/L against Streptococcus pneumoniae strains with GyrA and ParC mutations, and was the most active quinolone. BMS-284756 and its analogues had similar activity compared with ciprofloxacin and moxifloxacin against topoisomerase IV decatenation, but were three times more active than levofloxacin. The IC(50) of BMS-284756 for human topoisomerase II (hTopo II) was 3000 times higher than its IC(50) for DNA gyrase, and no whole-cell cytotoxicity was noted. Two analogues, BMS-340280 and BMS-340278, demonstrated moderate inhibition against hTopo II and cytotoxicity in the cellular assay. BMS-284756 demonstrated greater Gram-positive antibacterial activity and similar inhibition of targets compared with other fluoroquinolones, and more favourable selectivity compared with the other BMS-284756 analogues.
TL;DR: In this article, mutations in the quinolone resistance-determining region of topoisomerases GrlA, GrlB, GyrA, and GyrB together with MICs of six quinols were analyzed.
Abstract: Of 94 clinical isolates of Staphylococcus aureus (n = 51) and coagulase-negative staphylococci (CNS) (n = 43), mutations in the quinolone resistance-determining region of topoisomerases GrlA, GrlB, GyrA, and GyrB together with MICs of six quinolones were analyzed. Amino acid substitutions at identical residues (GrlA residues 80 and 84; GyrA residues 84 and 88) were found in S. aureus and CNS. Active efflux, as suggested by blocking by reserpine, contributed substantially to the resistance phenotype in some strains. Among ciprofloxacin, clinafloxacin, levofloxacin, nalidixic acid, trovafloxacin, and sparfloxacin, a 0.5-μg/ml concentration of sparfloxacin discriminated best between strains with two or three mutations and those with no mutations.
TL;DR: The intrinsically greater level of antibacterial activity and thus lower MICs of BMS-284756 observed at all resistance levels in this study may translate to coverage of these resistant pneumococcal strains in the clinic.
Abstract: Existing quinolones are known to target the type II topoisomerases in bacteria. In order to determine which of these targets are of key importance in Streptococcus pneumoniae treated with BMS-284756 (T-3811ME), a novel des-F(6) quinolone, resistant mutants were selected in several steps of increasing resistance by plating pneumococci on a series of blood agar plates containing serial twofold-increasing concentrations of drug. After incubation, colonies that arose were selected and passaged twice on antibiotic-containing media at the selection level. Mutants generally showed increases in resistance of four- to eightfold over the prior level of susceptibility. Mutants in the next-higher level of resistance were selected from the previous round of resistant mutants. Subsequently, chromosomal DNA was prepared from parental (R6) pneumococci and from at least three clones from each of four levels of increasing antibiotic resistance. Using PCR primers, 500- to 700-bp amplicons surrounding the quinolone resistance determining regions (QRDR) of gyrA, gyrB, parC, and parE genes were prepared from each strain. Internal primers were used to sequence both DNA strands in the regions of approximately 400 bp centered on the QRDR. Mutations identified with increasing levels of resistance included changes in GyrA at Ser-81 and Glu-85 and changes in ParC at Ser-79 and Asp-83. Changes in GyrB and ParE were not observed at the levels of resistance obtained in this selection. The resistance to comparator quinolones (levofloxacin, ciprofloxacin, and moxifloxacin) also increased in four- to eightfold steps with these mutations. The intrinsically greater level of antibacterial activity and thus lower MICs of BMS-284756 observed at all resistance levels in this study may translate to coverage of these resistant pneumococcal strains in the clinic.
TL;DR: For an in vitro mutant of Streptococcus pneumoniaeselected on moxifloxacin four- to eightfold- increased MICs of new fluoroquinolones, only a twofold-increased MIC of ciprofloxacIn, and a two fold-decreasedMIC of novobiocin were observed.
Abstract: For an in vitro mutant of Streptococcus pneumoniae selected on moxifloxacin four- to eightfold-increased MICs of new fluoroquinolones, only a twofold-increased MIC of ciprofloxacin, and a twofold-decreased MIC of novobiocin were observed. This phenotype was conferred by two mutations: Ser81Phe in GyrA and a novel undescribed His103Tyr mutation in ParE, outside the quinolone resistance-determining region, in the putative ATP-binding site of topoisomerase IV.
TL;DR: Overall, the quinolones are more rapidly bactericidal than vancomycin and the beta-lactam antibiotics.