Merck + Co., Inc.

Frederick M Kahan

Jean S Kahan

Robert T Goegelman

Sebastian Hernandez

Edward O Stapley

Helmut Kropp

Donald W Graham

Janos Kollonitsch

Edward F Rogers

Novel chemical compounds are provided which selectively inhibit the metabolism of dipeptidase (E.C.3.4.13.11) and therefore are useful in combination with antibacterial products. These chemical compounds are z-2-acylamino-3-monosubstituted propenoates.

Thienamycin renal peptidase inhibitors

A combination of a carbapenem of the formula: ##STR1## where R is H or CH.sub.3 and R.sup.1 is ##STR2## with a renal dipeptidase inhibitor is disclosed.

Combination of 2-substituted carbapenems with dipeptidase inhibitors

A novel antibacterial drug combination is provided, one component being a 2-substituted penem, and the other component is a dipeptidase (E.C.3.4.13.11) inhibitor. The dual-component combination is formulated so that 1 to 3 parts by weight of the penem are employed for 30 to 1 parts by weight of the inhibitor compound.

Combination of thienamycin-type antibiotics with dipeptidase inhibitors

Use of substituted propenoates to prevent nephrotoxicity of certain

Antibacterial compositions of thienamycin-type compounds and a dipeptidase (E.C.3.4.13.11) inhibitor.

A novel antibacterial drug combination is provided, one component being a fused ring .beta.-lactam, such as thienamycin and its semi-synthetic derivatives, and the other component is a dipeptidase (E.C. 3.4.13.11) inhibitor. The dual-component combination is formulated so that 1 to 3 parts by weight of the .beta.-lactam compound are employed for 30 to 1 parts by weight of the inhibitor compound.

The antibiotic thienamycin is active against both gram-positive and gram-negative bacteria. The antibiotic is produced by growing a newly-found and hitherto undescribed species of Streptomyces on suitable fermentation media.

Culture of Streptomyces cattleya

This invention relates to two new antibiotics, desacetyl 890A.sub.1 and desacetyl 890A.sub.3, active against both gram-positive and gram-negative bacteria, which are produced by treating 890A.sub.1 and 890A.sub.3, respectively, with an N-acetylthienamycin amidohydrolase produced by a soil microorganism isolated by enrichment techniques. This invention also relates to the process whereby N-acetylated structures of the thienamycin class of antibiotics such as N-acetyl thienamycin can be enzymatically deacetylated.

Process for enzymatic deacylation of antibiotics

This invention relates to the new antibiotic, desacetyl 890A.sub.10, active against both gram-positive and gram-negative bacteria, which is produced by treating 890A.sub.10 with an N-acetyl-890A.sub.10 amidohydrolase produced by a soil microorganism isolated by enrichment techniques. This invention also relates to the process by which 890A.sub.10 is enzymatically deacetylated.

Process for producing antibiotic desacetyl 890A.sub.10

The antibiotic N-acetyl thienamycin and its non-toxic pharmaceutically acceptable salts are active against both gram-positive and gram-negative bacteria. The antiobiotic is produced by growing a species of Streptomyces on suitable fermentation media or alternatively by acetylation of thienamycin.

Acetylthienamycin production

The antibiotic N-acetyl thienamycin and its non-toxic pharmaceutically acceptable salts are active against both gram-positive and gram-negative bacteria. The antibiotic is produced by growing a species of Streptomyces on suitable fermentation media or alternatively by acetylation of thienamycin.

N-acetyl thienamycin

A method is disclosed for cleaving N-acyl-thienamycin compounds to yield thienamycin. The new method disclosed herein utilizes enzymes which are penicillin amidohydrolases to treat the starting compounds resulting in the antibiotic thienamycin.

Enzymatic cleavage of N-acyl-thienamycins

The disclosed invention is directed to a process for preparing N-acyl-thienamycins from thienamycin and the appropriate acyl group by reacting the same in the presence of certain penicillin amidohydrolases capable of producing N-acyl thienamycins.

Production of N-acyl-thienamycins

Antibiotics

Novel antibacterial compositions are prepared by combining 3-fluoro-D-alanine-type compound, such as 3-fluoro-D-alanine and its deutero analogs, and salts and esters thereof, with a 3-fluoro-D-alanine autoantagonist-inhibitor such as cycloserine-type compound. The compositions demonstrate highly effective antibacterial action at high levels of dosage of the 3-fluoro-D-alanine component and, in addition, possess a remarkable synergistic antibacterial action.

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Rahway, NJ, United States of America

Frederick M Kahan