LM 427,a new spiropiperidylrifamycin: In vitro and in vivo studies.

Abstract

The spiropiperidylrifamycin LM 427 (4-deoxo-3,4-[2-spiro-N-isobutyl-4-piperidyl]-(1H)-imidazo-(2,5-dihydro)rifamycin S) displays a broad spectrum of potent antibacterial activity in vitro. In vivo it is particularly effective in the therapy of experimental tubercular infections of mice.Three schedules of treatment were employed and the best results were obtained when intermittent administrations were used (ED51 of LM 427; 7 times lower than rifampicin).LM 427 is well distributed in tissues of mice and rats, with lung concentrations 10-20 times higher than plasma levels.In a previous papery we described the antibacterial activity of a new class of rifamycin S derivatives: the spiropiperidylrifamycins.One member of this class (4-N-isobutylspiropiperidylrifamycin S; see structure below) whose code number is LM 427 (compound 11 in the earlier paper), showed remarkable activity against Mycobacterium tuberculosis in vitro and in vivo, together with an interesting profile of tissue distribution in rats.Recent research') carried out at the Center for Disease Control in Atlanta, Georgia, USA, demon- Portions of these data were presented at the 12th International Congress of Chemotherapy (Florence, 1981, Abstracts No. 956 & 960). Materials and MethodsIn Vitro Activity The minimal inhibitory concentration (MIC) on Gram-positive and Gram-negative bacteria, both standard and clinical isolates, was determined by the serial dilution technique in Bacto Antibiotic Medium No. 3 (Difco) supplemented with 1.5 % of Agar (Difco) for aerobic strains and in Bacto FTM (Difco) for the anaerobic strains. The inoculum consisted of about 105 cells per plate or per ml. Incubation was at 37°C for 1-2 days. The MIC on M. tuberculosis was determined by the serial dilution technique in Bacto Albumin Dubos Medium (Difco) inoculated with about 101 cells/ml and incubated for 7-10 days at 37°C.Rifampicin was taken as a reference compound. The antibiotics were dissolved in dimethylform-

Characterization of the porins of Campylobacter jejuni and Campylobacter coli and implications for antibiotic susceptibility

“…The literature shows that C. jejuni is more susceptible to doxycycline (mean MIC9Q, 11 ,ug ml-'; 15,17,24,29,55) than to tetracycline (mean MIC90, >24 ,ug ml-,; 5,9,24,26,29,47,53,55,56), which is less hydrophobic (27). C. jejuni is resistant to rifampin (mean MIC90, >87 ,g ml-'; 24, 47) but susceptible to the more hydrophobic derivative ansamycin (mean MIC90, 0.62 ,ug ml-'; 12,52). Similarly, the macrolides are taken up by the hydrophobic pathway (4) and are effective against C. jejuni (13).…”

“…Solutes (see Fig. 5) were used at concentrations of 25.5 mM (nonelectrolytes), 12.5 mM (sodium salts of monovalent anions), and 9 mM (sodium salts of divalent anions), which were in approximately the same ratio (3:1.5:1) used by Nikaido and Rosenberg (36). Triton X-100/EDTA-soluble protein (2 or 10 ,ug) was added to 400 ,ul of liposome suspension, and 20 p.l of this was diluted into 200 pd1 of the test solute to initiate the assay.…”

In vitro antimycobacterial activities of newly synthesized benzoxazinorifamycins

“…Second, RMP combination therapy exhibits relatively unsatisfactory efficacy against infections caused by M. avium complex (MAC) (4,21,27) because of its considerably weak in vitro activity against the MAC (3,22,23), possibly because of the permeability barrier of the organisms (7,20). Although other types of rifamycin derivatives, e.g., rifabutin (RBT) (2), rifapentine (1), FCE22807 (6), CGP40/469A (6), CGP-7040 (10), and P-DEA (10), have been developed and although the drugs have higher in vitro antimycobacterial activities than RMP (2,3,5,9,23,28), the drugs are generally not so active against MAC infection in humans, particularly immunocompromised hosts (12,14,29). Since MAC infections are increasing remarkably in immunocompromised hosts, particularly in AIDS patients (30), the need to develop new antimicrobial agents including rifamycin derivatives which have a strong activity against the MAC is urgent.…”

Antimycobacterial activity of a new rifamycin derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV (T9)

“…have been investigated for their activities against Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) in in vitro, macrophage, and animal models (1,3,8,10). In a similar attempt, the Chemical Pharmaceutical Research Institute, Sofia, Bulgaria, has developed a new rifamycin derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV, which was called T9 (Fig.…”