A-16686, a new antibiotic from Actinoplanes. II. Biological properties.

A-16686, a new glycoproteide antibiotic obtained from fermentation of an Actinoplanes strain, is active against Gram-positive aerobic and anaerobic bacteria; MIC values ranged from 0.016 to 2.0 micrograms/ml. A-16686 is bactericidal for growing cells of Staphylococcus aureus, S. epidermidis, Streptococcus faecalis, S. faecium, S. mutans, S. mitis and S. sanguis. There is no cross-resistance with clinically used antibiotics. A-16686, administered subcutaneously, is very effective in experimental S. pyogenes and S. pneumoniae septicemias in the mouse.

Antibacterial activity of DL 473, a new semisynthetic rifamycin derivative.

DL 473, a new semisynthetic rifamycin, was 2-10 times more active in vitro than rifampicin (RAMP) against several clinical isolates of Mycobacterium tuberculosis and only slightly less active than RAMP against Gram-positive and Gram-negative bacteria. It showed excellent therapeutic activity in mice in experimental infections caused by Staphylococcus aureus, Streptococcus pyogenes group A, Streptococcus pneumoniae and Klebsiella pneumoniae. In the experimental TB infection in the mouse DL 473 was clearly more active than isoniazide and RAMP, two of the most effective antitubercular drugs in current use. The LD50 in the mouse was significantly higher than that of RAMP and the half-life was about 5 times longer than that of RAMP.

Bbr 2778, an aza-anthracenedione endowed with preclinical anticancer activity and lack of delayed cardiotoxicity.

With the aim to provide second-generation anthracenedione analogues endowed with reduced side effects and a wider spectrum of action than mitoxantrone and doxorubicin, a large number of new molecules bearing nitrogen atoms in the chromophore was synthesized and screened in vitro and in vivo. From this screening, BBR 2778 (6,9-bis[(2-aminoethyl)amino] benzo[g]isoquinoline-5,10-dione dimaleate) emerged as the most interesting compound. BBR 2778 was tested in vitro on several murine and human tumor cell lines and showed cytotoxic potency lower than that of mitoxantrone and doxorubicin. BBR 2778 was more cytotoxic in leukemia and lymphoma cell lines than in solid tumor cell lines. Although against in vivo models BBR 2778 was less potent than mitoxantrone and doxorubicin, its antitumor activity was equal or superior (in certain tumor models) to that of the above standard compounds. In particular, BBR 2778 was curative against L1210 murine leukemia and YC-8 murine lymphoma. Moreover, it showed an antitumor activity comparable to that of mitoxantrone and doxorubicin on solid tumors. No cardiotoxic effect of BBR 2778 in animals not pretreated with anthracyclines was observed compared to standards. In light of its spectrum of activity and marked efficacy against lymphomas and leukemias over a wide dose range, together with its lack of delayed cardiotoxicity, BBR 2778 has been entered in clinical studies.

Teichomycin: in-vitro and in-vivo evaluation in comparison with other antibiotics.

Teichomycin, a new glycopeptide antibiotic with a spectrum of activity similar to that of vancomycin, was highly active against staphylococci, streptococci and Gram-positive anaerobes (Propionibacterium acnes, Clostridium perfringens and Cl. difficile). Ninety per cent of the Staphylococcus aureus and streptococcal strains, including enterococci, were inhibited by 0.4 mg/l; 90% of Staph. epidermidis strains were susceptible to 1.6 mg/l. Vancomycin was less active than teichomycin against all clinical isolates tested. Multiply resistant strains, including methicillin-resistant Staph. aureus, were all susceptible to teichomycin and vancomycin. Teichomycin was highly bactericidal for growing cells of staphylococci and Streptococcus pyogenes and moderately bactericidal for Str. faecalis. In mice, teichomycin was well absorbed upon subcutaneous administration and had a half-life of 2.5 h. It was very effective in curing experimental mouse septicemias caused by Gram-positive bacteria (ED50 values less than 1 mg/kg).