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Biomedical subjects

M J Rodriguez

Publications and source records attributed to M J Rodriguez.

28 records · Page 2Linked to original sources
PubMed1996

Semisynthetic glycopeptide antibiotics derived from LY264826 active against vancomycin-resistant enterococci.

Certain derivatives of the glycopeptide antibiotic LY264826 with N-alkyl-linked substitutions on the epivancosamine sugar are active against glycopeptide-resistant enterococci. Six compounds representing our most active series were evaluated for activity against antibiotic-resistant, gram-positive pathogens. For Enterococcus faecium and E. faecalis resistant to both vancomycin and teicoplanin, the MICs of the six semisynthetic compounds for 90% of the strains tested were 1 to 4 micrograms/ml, compared with 2,048 micrograms/ml for vancomycin and 256 micrograms/ml for LY264826. For E. faecium and E. faecalis resistant to vancomycin but not teicoplanin, the MICs were 0.016 to 1 micrograms/ml, compared with 64 to 1,024 micrograms/ml for vancomycin. The compounds were highly active against vancomycin-susceptible enterococci and against E. gallinarum and E. casseliflavus and showed some activity against isolates of highly vancomycin-resistant leuconostocs and pediococci. The MICs for 90% of the strains of methicillin-resistant Staphylococcus aureus tested were typically 0.25 to 1 micrograms/ml, compared with 1 microgram/ml for vancomycin. Against methicillin-resistant S. epidermidis MICs ranged from 0.25 to 2 micrograms/ml, compared with 1 to 4 micrograms/ml for vancomycin and 4 to 16 micrograms/ml for teicoplanin. The spectrum of these new compounds included activity against teicoplanin-resistant, coagulase-negative staphylococci. The compounds exhibited exceptional potency against pathogenic streptococci, with MICs of < or = 0.008 microgram/ml against Streptococcus pneumoniae, including penicillin-resistant isolates. In in vivo studies with a mouse infection model, the median effective doses against a challenge by S. aureus, S. pneumoniae, or S. pyogenes were typically 4 to 20 times lower than those of vancomycin. Overall, these new glycopeptides, such as LY307599 and LY333328, show promise for use as agents against resistant enterococci, methicillin-resistant S. aureus, and penicillin-resistant pneumococci.

Animals↗
PubMed1996

Relationship between structure and biological activity of novel R106 analogs.

The retro-aldol reaction at residue 8 of R106-1 produced a chemical handle, in the form of a sarcosine residue, that was amenable to classical aldol alkylation conditions. In vitro assay of several new hydroxylated analogs have shown that L isomers exhibit more potent antifungal activity than D isomers. However, all analogs exhibited a significant decrease in activity against Cryptococcus neoformans. By contrast, structural modifications of R 106 were tolerated by some Candida spp., but the potency of activity was diminished as compared to that of the natural product R106-1. The full structure-activity relationship of the new R106 analogs has provided important information about the steric and electronic requirements of binding to target receptors. Furthermore, comparison of the structural differences between R106-1 and other derivatives, suggested that the potential for hydrogen bonding (at residue 8) was a key structural feature that was required to maintain activity against Cryptococcus neoformans.

Anti-Bacterial Agents↗
PubMed1996

Reductive alkylation of glycopeptide antibiotics: synthesis and antibacterial activity.

Reductive alkylation of the A82846 family of glycopeptide antibiotics has the potential of producing seven products. N-Alkylation of the disaccharide amino function can be accomplished selectively, and offers the greatest increase in antibacterial activity. Products resulting from N-alkylation of LY264826 (A82846B) provide the most potent derivatives as compared to other members of this class of antibiotics. Two of these derivatives, LY307599 and LY333328 are approximately 500 times more active than vancomycin against vancomycin-resistant enterococci.

Alkylation↗
PubMed1995

Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB.

Echinocandin B (ECB) is a lipopeptide composed of a complex cyclic peptide acylated at the N-terminus by linoleic acid. Enzymatic deacylation of ECB provided the peptide "nucleus" as a biologically inactive substrate from which novel ECB analogs were generated by chemical reacylation at the N-terminus. Varying the acyl group revealed that the structure and physical properties of the side chain, particularly its geometry and lipophilicity, played a pivotal role in determining the antifungal potency properties of the analog. Using CLOGP values to describe and compare the lipophilicities of the side chain fragments, it was shown that values of > 3.5 were required for expression of antifungal activity. Secondly, a linearly rigid geometry of the side chain was the most effective shape in enhancing the antifungal potency. Using these parameters as a guide, a variety of novel ECB analogs were synthesized which included arylacyl groups that incorporated biphenyl, terphenyl, tetraphenyl, and arylethynyl groups. Generally the glucan synthase inhibition by these analogs correlated well with in vitro and in vivo activities and was likewise influenced by the structure of the side chain. These structural variations resulted in enhancement of antifungal activity in both in vitro and in vivo assays. Some of these analogs, including LY303366 (14a), were effective by the oral route of administration.

Acylation↗
PubMed1988

Cadang-cadang disease of coconut palm.

Cadang-cadang disease has caused the death of over 30 million coconut palms, and no control measures are known. The causal viroid is the smallest known pathogen. Field diagnostic tests will soon be developed to allow mapping of the distribution and spread of the viroid and this should lead to the identification of appropriate control measures.

Base Sequence↗
PubMedDate not supplied

[Immobilization of Citrobacter freundii cells with tyrosine phenol-lyase activity by entrapment in natural gels].

A comparative study on immobilization of Citrobacter freundii cells by entrapment in carrageenan, agar, agar-agar, and gelatin gels (5, 10, and 15%) was carried out. Gelatin gels were treated with glutaraldehyde to make them more rigid. As a result, the tyrosine phenol-lyase activity of these samples was less than that of free cells (about 40%). The yield of TP-lyase activity was 40--60% when cells were immobilized in 5% and 7% agar and agar-agar gels. The cells entrapped in carrageenan gels, the concentration of which was varied from 2 to 10%, possessed the highest tyrosine phenol-lyase activity (up to 90%). The efficiency of cell entrapment was high for all the carrier and equal to 70--90%. The plastic strength and swelling of the above gels, as well as the phenol adsorption on the carriers and the release of the bacterial cells from them were studied under the conditions of tyrosine phenol-lyase reaction.

Adsorption↗