In Vitro and In Vivo Activities of a Novel Cephalosporin, BMS-247243, against Methicillin-Resistant and -Susceptible Staphylococci

Fung‐Tomc, Joan; Clark, Junius M.; Minassian, Beatrice; Pucci, Michael J.; Tsai, Yuan-Hwang; Gradelski, Elizabeth; Lamb, Lucinda; Medina, Ivette; Huczko, E; Kolek, B; Chaniewski, Susan; Ferraro, Cheryl; Washo, Thomas; Bonner, Daniel P.

doi:10.1128/aac.46.4.971-976.2002

Cited by 41 publications

(27 citation statements)

References 14 publications

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“…[2][3][4][5][6] With the increase in resistance of bacteria to antibiotic treatment, attention was given on developing novel approaches to antimicrobial therapy. [7][8][9][10][11][12][13] We have previously reported the significant antifungal activity of a series of sulfonamide-1,2,4-triazole derivatives against a series of micromycetes, compared to the commercial fungicide bifonazole. These compounds have also shown a comparable bactericidal effect to that of streptomycin but better activity than chlorampenicol respectively against various bacteria.…”

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Sulfonamide-1,2,4-thiadiazole Derivatives as Antifungal and Antibacterial Agents: Synthesis, Biological Evaluation, Lipophilicity, and Conformational Studies

et al. 2010

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Bacterial infections have increased dramatically in recent years. Bacteria have been the cause of some of the most deadly diseases and widespread epidemics in human civilization.1) Moreover, the widespread use and misuse of antibiotics has caused bacterial resistance. Some of these resistant strains, such as vancomycin-resistant enterococci (VRE) and multidrug resistant Staphylococcus aureus (MRSA), are capable of surviving the effects of most, if not all, antibiotics currently in use. [2][3][4][5][6] With the increase in resistance of bacteria to antibiotic treatment, attention was given on developing novel approaches to antimicrobial therapy. [7][8][9][10][11][12][13] We have previously reported the significant antifungal activity of a series of sulfonamide-1,2,4-triazole derivatives against a series of micromycetes, compared to the commercial fungicide bifonazole. These compounds have also shown a comparable bactericidal effect to that of streptomycin but better activity than chlorampenicol respectively against various bacteria. 14)Thiadiazoles belong to the wider category of imidazole and triazole synthetic antifungal drugs which are designed to inhibit the enzyme cytochrome P450 14a-demethylase and inhibit the conversion of lanosterol to ergosterol, which is required in fungal cell membrane synthesis.1,3,4-Thiadiazoles are known to possess antibacterial and antifungal properties similar to those of well known sulphonamide drugs.15) Thus, the 1,3,4-thiadiazoles exhibit a broad spectrum of biological activities possibly due to the presence of the toxophoric -N-C-S moiety.16) Prompted by these observations and in continuation of our search for bioactive molecules, we designed the synthesis of a series of novel sulfonamide-1,3,4-thiadiazoles, emphasizing, in particular, on the strategy of combining two chemically different but pharmacologically compatible molecules (the sulfonamide nucleus and the five member heterocycle) in one frame, in order to study their antibacterial and antifungal activities.Chemistry The synthetic pathway followed for the preparation of the title compounds was accomplished as shown in Chart 1.Starting from ethyl(2-chlorosulfonyl-4,5-dimethoxyphenyl)acetate (1) 17,18) by reaction with secondary aliphatic amines in anhydrous benzene the corresponding sulfonamides Results and DiscussionBiological Evaluation and Lipophilicity Studies The results of antibacterial and antifungal activity of compounds 5a-m against a panel of selected Gram positive, Gram negative bacteria and fungi are presented in Tables 1 and 2 in comparison with those of the reference drugs ampicillin and streptomycin, bifonazole and ketoconazole respectively.Results of antibacterial activity of compounds (Table 1) show that the minimum inhibitory concentration (MIC) of compounds varies in the range of 0.92-4.6ϫ10 Ϫ2 mmol/ml, while minimum bactericidal concentration (MBC) varies between 1. 75-9.20ϫ10 Ϫ2 mmol/ml. Compounds 5a, 5b, 5c and 5g showed the lowest antibacterial activity among the tested compounds with 5a being t...

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Sulfonamide-1,2,4-thiadiazole Derivatives as Antifungal and Antibacterial Agents: Synthesis, Biological Evaluation, Lipophilicity, and Conformational Studies

et al. 2010

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“…The beta-lactam antibiotics that are used clinically do not bind to PBP 2a at therapeutic concentrations and therefore lack efficacy against infections caused by methicillin-resistant staphylococci. With the solution of the crystal structure of a soluble derivative of PBP 2a, low-affinity binding can be attributed at least in part to an energetically unfavorable acylation reaction of the active site serine due to the slippage of the beta-lactam molecule within a long groove that serves as the initial, reversible binding site in the formation of the Michaelis-Menten complex (16).Several cephalosporin and carbapenem derivatives that bind to PBP 2a with 100-fold or higher affinities than those of other beta-lactams and which are active in vitro and in vivo against methicillin-resistant staphylococci have been synthesized (2,6,7,13,20). These compounds have in common a relatively extended side chain attached to the ␣ ring of the beta-lactam compound core (3, 16).…”

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“…Several cephalosporin and carbapenem derivatives that bind to PBP 2a with 100-fold or higher affinities than those of other beta-lactams and which are active in vitro and in vivo against methicillin-resistant staphylococci have been synthesized (2,6,7,13,20). These compounds have in common a relatively extended side chain attached to the ␣ ring of the beta-lactam compound core (3, 16).…”

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“…This structural feature permits the molecule to be positioned within the groove in such a way that the acylation reaction proceeds at a rate more rapid than that in its lower-affinity relatives. Two of these compounds, BAL 9141 and RWJ 54428, have been tested in phase I trials with humans (7,17). It is quite likely that within the next few years a PBP 2a-binding beta-lactam will become available for clinical use.…”

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PBP 2a Mutations Producing Very-High-Level Resistance to Beta-Lactams

Katayama

Zhang

Chambers

2004

Antimicrob Agents Chemother

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Resistance to the beta-lactam class of antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) is mediated by PBP 2a, a synthetic bacterial cell wall penicillin-binding protein with a low affinity of binding to beta-lactams that is encoded by mecA. Beta-lactams that bind to PBP 2a with a high affinity and that are highly active against MRSA are under development. The potential for the emergence of resistance to such compounds was investigated by passage of homogeneous MRSA strain COL in L-695,256, an investigational carbapenem. A highly resistant mutant, COL52, expressed PBP 2a in which a two-amino-acid deletion mutation and three single-amino-acid substitution mutations were present. To examine the effects of these mutations on the resistance phenotype and PBP 2a production, plasmids carrying (i) PBP 2a with two or three of the four mutations, (ii) wild-type PBP 2a, or (iii) COL52 PBP 2a were introduced into methicillin-susceptible COL variants COLnex and COL52ex, from which the staphylococcus cassette chromosome mec (SCCmec) has been excised, as indicated by the "ex" suffix. Two amino acids substitutions, E3K 237 within the non-penicillinbinding domain and V3E 470 near the SDN 464 conserved penicillin-binding motif in the penicillin-binding domain in COL52, were important for high-level resistance. The highest level of resistance was observed when all four mutations were present. The emergence of PBP 2a-mediated resistance to beta-lactams that bind to PBP 2a with a high affinity is likely to require multiple mutations in mecA; chromosomal mutations appear to have a minor role.Staphylococcal resistance to the beta-lactam class of antibiotics, termed methicillin resistance, is mediated by PBP 2a, a low-affinity penicillin-binding protein (PBP). The beta-lactam antibiotics that are used clinically do not bind to PBP 2a at therapeutic concentrations and therefore lack efficacy against infections caused by methicillin-resistant staphylococci. With the solution of the crystal structure of a soluble derivative of PBP 2a, low-affinity binding can be attributed at least in part to an energetically unfavorable acylation reaction of the active site serine due to the slippage of the beta-lactam molecule within a long groove that serves as the initial, reversible binding site in the formation of the Michaelis-Menten complex (16).Several cephalosporin and carbapenem derivatives that bind to PBP 2a with 100-fold or higher affinities than those of other beta-lactams and which are active in vitro and in vivo against methicillin-resistant staphylococci have been synthesized (2,6,7,13,20). These compounds have in common a relatively extended side chain attached to the ␣ ring of the beta-lactam compound core (3, 16). This structural feature permits the molecule to be positioned within the groove in such a way that the acylation reaction proceeds at a rate more rapid than that in its lower-affinity relatives. Two of these compounds, BAL 9141 and RWJ 54428, have been tested in phase I trials with humans (7, 17). It is qui...

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“…It has been shown to have activity against a wide range of clinical isolates (1,7,12,34), and in particular, garenoxacin has been shown to have good activity against Staphylococcus aureus, both methicillin sensitive and resistant (6), and the respiratory pathogens Streptococcus pneumoniae (26), Haemophilus influenzae, and Moraxella catarrhalis (8). The activity of garenoxacin has been further assessed against strains of S. aureus with specific topoisomerase mutations (21), and more recently, it has been shown that garenoxacin has similar potency against both topoisomerase IV and gyrase (16) (dual-targeting quinolone), thus requiring mutations in both topoisomerases for resistance to occur (29).…”

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Antimicrobial Activities of Garenoxacin (BMS 284756) against Asia-Pacific Region Clinical Isolates from the SENTRY Program, 1999 to 2001

Christiansen

Bell

Turnidge

et al. 2004

Antimicrob Agents Chemother

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Between 1999 and 2001, 16,731 isolates from the Asia-Pacific Region were tested in the SENTRY Program for susceptibility to six fluoroquinolones including garenoxacin. Garenoxacin was four-to eightfold less active against Enterobacteriaceae than ciprofloxacin, although both drugs inhibited similar percentages at 1 g/ml. Garenoxacin was more active against gram-positive species than all other fluoroquinolones except gemifloxacin. For Staphylococcus aureus, oxacillin resistance was high in many participating countries (Japan, 67%; Taiwan, 60%; Hong Kong, 55%; Singapore, 52%), with corresponding high levels of ciprofloxacin resistance (57 to 99%) in oxacillin-resistant S. aureus (ORSA). Of the ciprofloxacin-resistant ORSA isolates, the garenoxacin MIC was >4 g/ml for only 9% of them. For Streptococcus pneumoniae, penicillin nonsusceptibility and macrolide resistance were high in many countries. No relationship was seen between penicillin and garenoxacin susceptibility, with all isolates being susceptible at <2 g/ml. There was, however, a partial correlation between ciprofloxacin and garenoxacin MICs. For ciprofloxacin-resistant isolates for which garenoxacin MICs were 0.25 to 1 g/liter, mutations in both the ParC and GyrA regions of the quinolone resistance-determining region could be demonstrated. No mutations conferring high-level resistance were detected. Garenoxacin shows useful activity against a wide range of organisms from the Asia-Pacific region. In particular, it has good activity against S. aureus and S. pneumoniae, although there is evidence that low-level resistance is present in those organisms with ciprofloxacin resistance.

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In Vitro and In Vivo Activities of a Novel Cephalosporin, BMS-247243, against Methicillin-Resistant and -Susceptible Staphylococci

Cited by 41 publications

References 14 publications

Sulfonamide-1,2,4-thiadiazole Derivatives as Antifungal and Antibacterial Agents: Synthesis, Biological Evaluation, Lipophilicity, and Conformational Studies

Sulfonamide-1,2,4-thiadiazole Derivatives as Antifungal and Antibacterial Agents: Synthesis, Biological Evaluation, Lipophilicity, and Conformational Studies

PBP 2a Mutations Producing Very-High-Level Resistance to Beta-Lactams

Antimicrobial Activities of Garenoxacin (BMS 284756) against Asia-Pacific Region Clinical Isolates from the SENTRY Program, 1999 to 2001

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