Affinity of Tomopenem (CS-023) for penicillin-binding proteins in Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa.

Tomopenem (formerly CS-023), a novel 1beta-methylcarbapenem, exhibited high affinity for penicillin-binding protein (PBP) 2 in Staphylococcus aureus, PBP 2 in Escherichia coli, and PBPs 2 and 3 in Pseudomonas aeruginosa, which are considered major lethal targets. Morphologically, tomopenem induced spherical forms in E. coli and short filamentation with bulges in P.

Potent in vitro activity of tomopenem (CS-023) against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa.

Tomopenem (formerly CS-023) is a novel 1beta-methylcarbapenem with broad-spectrum coverage of gram-positive and gram-negative pathogens. Its antibacterial activity against European clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa was compared with those of imipenem and meropenem. The MICs of tomopenem against MRSA and P.

In vitro and in vivo antibacterial activities of CS-023 (RO4908463), a novel parenteral carbapenem.

CS-023 (RO4908463, formerly R-115685) is a novel 1beta-methylcarbapenem with 5-substituted pyrrolidin-3-ylthio groups, including an amidine moiety at the C-2 position. Its antibacterial activity was tested against 1,214 clinical isolates of 32 species and was compared with those of imipenem, meropenem, ceftazidime, ceftriaxone, ampicillin, amikacin, and levofloxacin. CS-023 exhibited a broad spectrum of activity against gram-positive and -negative aerobes and anaerobes, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae (PRSP), beta-lactamase-negative ampicillin-resistant Haemophilus influenzae, and Pseudomonas aeruginosa.

Antifungal activities of R-135853, a sordarin derivative, in experimental candidiasis in mice.

The activities of R-135853, a novel sordarin derivative that possesses a 1,4-oxazepane ring moiety, were evaluated in vitro and in vivo. R-135853 exhibited potent in vitro activities against Candida albicans (fluconazole-susceptible strains), Candida glabrata, Candida tropicalis, and Cryptococcus neoformans, with MICs at which 90% of isolates were inhibited of 0.03, 1, 0.

Activity of capuramycin analogues against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare in vitro and in vivo.

Objectives: The antimycobacterial activities of RS-112997, RS-124922 and RS-118641, three capuramycin analogues that inhibit phospho-N-acetylmuramyl-pentapeptide translocase, were tested against clinical isolates of Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare.

Methods And Results: MICs were determined by the broth microdilution method using a modified Middlebrook 7H9 broth. RS-118641 was the most potent compound overall.

[Strategy for research and development of antifungal agents].

The incidence of deep-seated mycosis has recently been increasing, while the number of clinically available antifungal agents is very limited and each agent has some drawbacks. We focused on the triazole class that is known to have good profiles as antifungal agents. After researching them, we found that CS-758 had excellent profiles in terms of antifungal spectrum, activity, and safety.

Synthesis and antimycobacterial activity of capuramycin analogues. Part 2: acylated derivatives of capuramycin-related compounds.

Acylated derivatives of capuramycin and A-500359A were synthesized and tested for antimycobacterial activity. Compound 20 having a decanoyl group showed very potent activity.

Synthesis and antimycobacterial activity of capuramycin analogues. Part 1: substitution of the azepan-2-one moiety of capuramycin.

Capuramycin analogues with a variety of substituents in place of the azepan-2-one moiety were synthesized from A-500359E and were tested for their translocase I inhibitory activity and in vitro antimycobacterial activity. Phenyl-type moieties were found to be effective substituents for capuramycin analogues.

Synthesis and structure-activity relationships of novel parenteral carbapenems, CS-023 (R-115685) and related compounds containing an amidine moiety.

In order to design a new parenteral 1beta-methylcarbapenem antibiotic which has a broad antibacterial spectrum and improved plasma half-life, a series of 1beta-methylcarbapenems with 5-substituted pyrrolidine-3-ylthio groups including an amidine moiety at the C-2 position have been synthesized and structure-activity relationships were investigated. Among those carbapenem derivatives, CS-023 (R-115685) showed a broad spectrum and excellent antibacterial activity against Gram-positive and Gram-negative bacteria. This compound also showed sufficient dehydropeptidase-I (DHP-I) stability and high urinary recovery in animals after subcutaneous administration without cilastatin, a DHP-I inhibitor.

Genetic basis for differential activities of fluconazole and voriconazole against Candida krusei.

Invasive infections caused by Candida krusei are a significant concern because this organism is intrinsically resistant to fluconazole. Voriconazole is more active than fluconazole against C. krusei in vitro.

[Antibacterial activity of cefpodoxime against clinical isolates in 2000 and 2001].

As the post-marketing surveillance of cefpodoxime proxetil (Banan), MICs of cefpodoxime (CPDX, an active form of Banan) against 1090 clinical isolates of 22 species from 15 medical institutions all over Japan from June 2000 to March 2001 were measured using the broth microdilution method approved by the Japanese Society of Chemotherapy and compared with those of oral cephem antibacterials, cefaclor, cefdinir, cefditoren, and cefcapene. In this study, remarkable change in the activity of CPDX was observed in Streptococcus pneumoniae and Haemophilus influenzae compared with the susceptibility in the studies before Banan was launched. This cause is considered to be the increase in the incidence of the following resistant strains: penicillin-intermediate S.

[Antibacterial activity of panipenem against clinical isolates in 2000 and 2001].

As the post-marketing surveillance of panipenem/betamipron (Carbenin), MICs of panipenem (PAPM) against 1355 clinical isolates of 28 species from 15 medical institutions all over Japan from June 2000 to March 2001 were measured using the broth microdilution method approved by the Japanese Society of Chemotherapy and compared with those of parenteral carbapenem antibacterials, imipenem (IPM) and meropenem (MEPM), and parenteral cephem antibacterials, cefozopran, cefepime, and sulbactam/cefoperazone. The activity of PAPM was comparable to that of IPM against almost all species tested. Compared with MEPM, PAPM was more active against Gram-positive bacteria and Bacteroides spp.

Efficacy of CS-758, a novel triazole, against experimental fluconazole-resistant oropharyngeal candidiasis in mice.

The therapeutic efficacy of CS-758, a novel triazole, was evaluated against experimental murine oropharyngeal candidiasis induced by Candida albicans with various susceptibilities to fluconazole. Against infections induced by strains with various susceptibilities to fluconazole, the efficacy of fluconazole was strongly correlated with the MIC of fluconazole, as measured by the NCCLS method, and agreed with the NCCLS interpretive breakpoints, suggesting that the efficacies of new drugs could be predicted by using this model. The results of the fungal burden study corresponded with the results of the histopathological study.

Synthesis and evaluation of novel pyrrolidinyl sordaricin derivatives as antifungal agents.

N-Benzyl pyrrolidinyl sordaricin derivatives have been synthesized from cis-4-hydroxy-D-proline in a stereocontrolled manner. These compounds maintained moderate antifungal activity against several pathogenic fungal strains. Their MIC values against Candida albicans were in the range of 0.

Contribution of Candida albicans ALS1 to the pathogenesis of experimental oropharyngeal candidiasis.

We investigated the contribution of Candida albicans ALS1, which encodes a candidal adhesin, to the pathogenesis of experimental murine oropharyngeal candidiasis. Our results indicate that the ALS1 gene product is important for the adherence of the organism to the oral mucosa during the early stage of the infection.

[Rapid bactericidal activities of carbapenems against Pseudomonas aeruginosa in simulating human plasma concentrations].

The rapid bactericidal activities of panipenem (PAPM), imipenem (IPM), and meropenem (MEPM) against Pseudomonas aeruginosa were investigated by using in vitro pharmacodynamic model simulating the human plasma concentrations after intravenous drip infusion at 500 mg for 0.5 hours. Against P.

Synthesis and evaluation of N-substituted 1,4-oxazepanyl Sordaricins as selective fungal EF-2 inhibitors.

Sordaricin analogues possessing 6-methoxy-7-methyl-1,4-oxazepane moiety instead of the sugar part were synthesized and evaluated. It was found that N-substituents on the oxazepane ring had influence on biological activity. In particular, N-(2-methylpropenyl) derivative 12p exhibited potent in vitro antifungal activity.

Synthesis of Sordaricin analogues as potent antifungal agents against Candida albicans.

Sordaricin derivatives possessing a cyclohexane ring appendage attached via an ether, thioether, amine, oxime, ester or amide linkage were synthesized and their antifungal activity was evaluated in vitro. Compounds containing a thioether bond or an oxime bond as a linkage exhibited potent MICs (< or = 0.125 microg/mL) against four Candida albicans strains including azole-low-susceptible strains.

In vitro and in vivo activities of CS-758 (R-120758), a new triazole antifungal agent.

The activity of CS-758 (R-120758), a new triazole antifungal agent, was evaluated and compared with those of fluconazole, itraconazole, and amphotericin B in vitro and with those of fluconazole and itraconazole in vivo. CS-758 exhibited potent in vitro activity against clinically important fungi. The activity of CS-758 against Candida spp.