1. Eur J Biochem ;151(2):209-16.( 1985)

Second lytic target of beta-lactam compounds that have a terminal D-amino acid residue.

Tsuruoka T, Tamura A, Miyata A, Takei T, Inouye S, Matsuhashi M.

A new biochemical mechanism of lysing bacterial cells by treatment with certain beta-lactam compounds that possess a terminal D-amino acid moiety in their side chain was demonstrated. The two functions of the molecule, the beta-lactam and terminal D-amino acid moiety, are both involved in the activity of lysing gram-negative bacteria, which is characterized by very rapid lysis of the cells in the first few hours after their contact with the compound. This mechanism was proved by studies on one such compound, named MT-141, which contains a terminal D-cysteine moiety with free amino and carboxyl groups in the 7 beta-side chain of the 7 alpha-methoxy-cephalosporin skeleton. This compound bound to the cell-wall peptidoglycan of Escherichia coli through the D-amino group of its terminal D-amino acid moiety and this seemed to cause rapid cell lysis. Both activities, of binding to peptidoglycan and of causing rapid cell lysis, were inhibited by certain D-amino acids, but not by L-amino acids. Mutants were isolated that had simultaneously gained decreased sensitivity to this kind of beta-lactam compound and supersensitivity to globomycin, an inhibitor of formation of lipoproteins which function in linking the peptidoglycan to the outer membrane. These results suggest that binding of the terminal D-amino acid moiety of the beta-lactam compound to peptidoglycan somehow influences formation of the linkage between the outer membrane and the peptidoglycan and consequently enhances the cell lytic activity of the beta-lactam portion of the molecule.

2. Drugs Exp Clin Res;11(11):771-80.( 1985)

Comparative bactericidal and morphological effects of five cephamycins on cells of three gram-negative bacilli at decreasing drug concentrations.

Goi H, Watanabe T, Miyauchi K, Kazuno Y, Inouye S.

The bactericidal and morphological effects under drug-decreasing conditions of cefminox (MT-141), cefoxitin, cefmetazole, cefotetan and latamoxef were compared on Klebsiella pneumoniae PCl-602, Escherichia coli No. 29 and Serratia marcescens No. 1 cells. A new drug-decreasing method was developed by the use of an antibiotic removal device. Cefminox displayed an earlier onset and a higher rate of bactericidal action than the other cephamycins against the test organisms, although the minimum inhibitory concentrations of cefminox were similar to or higher than those of the other drugs. Morphologically, cefminox caused rapid lysis of the cells without filamentation, whereas the reference cephamycins caused mainly elongation of the cells under the test conditions. Frequent formation of multiple bulges on cells exposed to cefminox was observed in an isotonic medium.

3. Antimicrob Agents Chemother ;26(5):722-9.( 1984 )

In vitro and in vivo antibacterial activities of MT-141, a new semisynthetic cephamycin, compared with those of five cephalosporins.

Inouye S, Goi H, Watanabe T, Hara T, Miyauchi K, Yoshida T, Kazuno Y, Kadosawa H, Hirano F, Kawaharajo K, et al.

The in vitro and in vivo antibacterial activities of MT-141 were compared with those of cefoxitin, cefmetazole, moxalactam, cefotaxime, and cefoperazone. The MICs of MT-141 for 90% of bacterial isolates were lower than the reference drugs against clinical isolates of Campylobacter jejuni, Clostridium difficile, and Bacteroides fragilis, whereas against clinical isolates of other gram-positive, gram-negative, and anaerobic bacteria, the MICs of MT-141 were similar to or higher than those of the reference drugs. In contrast, the bactericidal activity of MT-141 after 6- and 24-h exposures was superior to all of the reference drugs against 9 to 10 of the 12 bacterial strains studied, including Escherichia coli, Klebsiella pneumoniae, Salmonella enteritidis, indol-positive Proteus species, Serratia marcescens, Yersinia enterocolitica, Pseudomonas cepacia, and Clostridium perfringens. In the treatment of systemic infections in mice, MT-141 was again superior against 9 of the 12 strains tested, showing a good correlation with the bactericidal activity. It was found that the 50% effective doses of the six cephalosporins studied correlated better with the MBCs than with the MICs. As the serum levels of MT-141 in mice after subcutaneous administration were similar to those of the reference drugs, it was concluded that the bactericidal activity of MT-141 was a dominant factor in its in vivo activity.

4. J Antimicrob Chemother ;15(6):701-14.( 1985 )

In-vitro and in-vivo activities of a novel cephamycin MT-141 against the Bacteroides fragilis group in comparison with six cephem antibiotics.

Kasai T, Hara T, Tamura A, Kazuno Y, Inouye S, Goto S, Kuwahara S.

MT-141 inhibited 90% of the clinical isolates of Bacteroides fragilis at 3.13 mg/l, whereas six reference cephem antibiotics inhibited them at 12.5- greater than 100 mg/l. MT-141 was stable to the Bacteroides beta-lactamases, but the stability alone could not explain the potent activity of MT-141 against the other Bacteroides spp., which produced only small amounts of beta-lactamase, but were resistant to other cephem antibiotics. MT-141 exhibited a higher killing rate and more potent in-vivo efficacy than the reference cephem antibiotics against Bact. fragilis No. 36 combined with Escherichia coli No. 29. In conclusion, the in-vitro and in-vivo anti-bacteroides activities of MT-141 ranked first among those of the cephem antibiotics compared

5. Int J Clin Pharmacol Ther ;33(3):149-55.( 1995 )

Postmarketing surveillance on side-effects of cefminox sodium (Meicelin).

Mayama T, Koyama Y, Sebata K, Tanaka Y, Shirai S, Sakai H.

Pharmaceutical Information and Regulatory Affairs, Meiji Seika Kaisha, Ltd., Tokyo, Japan.

A postmarketing surveillance of cefminox sodium (Meicelin, CMNX) for intravenous injection was conducted for about 4 years from August 1987 through June 1991, and 13,431 patients were followed up to evaluate the safety of the drug. The incidence of side-effects was 1.76%. By organ, the most frequently observed were hepatic and of the bile duct system (0.87%) followed by those on leukocytes and reticuloendothelial system (0.24%), skin and adnexa (0.24%) and digestive tract (0.16%) indicating a tendency similar to that of other injectable cephalosporins. The incidence of the side-effects among elderly patients (65 years old or older) was 2.12%, whereas among patients 64 years old or younger it was 1.58% with no significant differences between the two groups. No side-effects specific to the elderly were observed. Among children 15 years old or younger the incidence was 0.59%, which was lower than that for patients 16 years old or older (1.90%). Potential side-effects on pregnant women (n = 101) and their babies were also checked. No side-effects occurred among the 52 pregnant women evaluated and no abnormalities were detected in their babies who were followed up for up to 4 years. Cefminox is thus considered to be a highly safe cephalosporin antibiotic.

6. Antimicrob Agents Chemother ;36(1):223-6. (1992)

Effect of inoculum size on bacteriolytic activity of cefminox and four other beta-lactam antibiotics against Escherichia coli.

Soriano F, Edwards R, Greenwood D.

Department of Microbiology, University Hospital, Queen's Medical Centre, Nottingham, United Kingdom.

MICs and turbidimetric experiments revealed a negligible inoculum effect with two Escherichia coli strains exposed to cefminox and cefoxitin, whereas a marked inoculum effect was revealed after exposure to cefotaxime, ceftizoxime, and imipenem. The activities of the cephamycins were associated with spheroplast formation and bacteriolysis at concentrations close to the MIC, whereas the other agents induced the formation of filaments or, in the case of imipenem, rounded cells.

7. J Antimicrob Chemother ;15(2):159-71. (1985)

The bacteriolytic action of MT-141, a new cephamycin antibiotic, on gram-negative bacteria.

Tsuruoka T, Yamada Y, Goi H, Miyauchi K, Miyata A, Inouye S, Ishino F, Hirata A, Matsuhashi M.

MT-141, a new cephamycin (7 alpha-methoxy-cephalosporin) antibiotic with a D-cysteine moiety in its 7 beta-side chain, has binding affinities to penicillin-binding proteins of Escherichia coli and an inhibitory action on their transpeptidase activity similar to those of other structurally related cephamycins. Yet this antibiotic was found to exert an exceedingly strong and rapid lytic action on sensitive Gram-negative bacteria such as E. coli, Klebsiella pneumoniae, Serratia marcescens and Salmonella enteritidis. Not only rapidly growing cells, but also slowly growing dense cells of the above bacteria could be lysed by this antibiotic at low concentrations. In the presence of 20% sucrose, low concentrations of MT-141 induced smooth-surfaced single and twin bulges of the putative growth zone of the cells and irregularly orientated rough-surfaced bulges. Probably the 7 beta-side chain structure of this antibiotic is involved in its rapid and strong bacteriolytic action.

8. J Antibiot (Tokyo) ;37(11):1403-13. (1984 )

Structure-activity relationships on the terminal D-amino acid moiety of a novel cephamycin MT-141.

Inouye S, Tsuruoka T, Goi H, Iwamatsu K, Miyauchi K, Ishii T, Tamura A, Kazuno Y, Matsuhashi M.

The effect of chemical modification of the D-amino acid function, which represents the C-7 beta substituent of cephamycin MT-141 on in vitro antibacterial activity was examined. MT-141 was more active on Gram-negative organisms than Gram-positive ones. It showed strong bacteriolytic activity on Gram-negative organisms. Lysis of Escherichia coli K-12 strain JE1011 treated with a low concentration of this antibiotic was preceded by frequent formation of multiple bulges from the cells. Amidation or decarboxylation, removing the acidic function from the D-amino acid of MT-141, resulted in an increase in activity against Gram-positive bacteria, and a decrease against Gram-negative ones. Cells treated with the amide or the decarboxylate did not form multiple bulges but formed single bulges. N-Acetylation of the D-amino acid moiety removing the basic function, caused a marked drop in activity against both Gram-positive and Gram-negative bacteria. The bacteriolytic activity on E. coli was reduced, and cells treated with the N-acetate became filamentous. Conversion of the D-amino acid function of MT-141 to the L configuration caused a moderate drop in activity against both Gram-positive and Gram-negative organisms. Both bacteriolytic and bactericidal activities against E. coli were reduced in the L-congener. Cefoxitin, cefmetazole and latamoxef used as reference antibiotics were less active than MT-141 in the bactericidal activity against E. coli, and induced single bulge formation or filamentation of the cells around MIC levels. Cell-surface permeability, stability to beta-lactamases, and binding affinity to PBPs of E. coli did not differ between MT-141 and its derivatives.

9. 최신의학 ;32(11) (1989)

호흡기 감염증에 대한 MT-141(Cefminox, Meicelin®)의 임상적 효과에 대한 고찰.

국립의료원 내과학 교실: 박 원, 이흥순, 이학중

국립의료원 세균과: 정경은

The clinical investigation on a new cephamycin, MT-141, for the treatment of respiratory tract infections such as pneumonia, acute mucopurulent bronchitis and acutely exacerbated chronic bronchitis was done.

Total number of patients who received MT-141 was 33 and 3 patients were excluded from the evaluation of MT-141 effectiveness because two patients were proved to have pulmonary tuberculosis and one patient received MT-141 less than 3 days.

In remaining 30 patient, 18 of them were diagnosed as pneumonia and 12 patients as bronchitis. Overall clinical effectiveness in 30 patients was 76.7%(23 patients).

It was effective in 12 pneumonia patients(66.7%) and 11 patints(91.7%) of bronchitis, respectively.

Out of 33 patients, 4 patients showed elevated serum liver enzyme level during or just after MT-141 treatment and one patient showed thrombocytopenia, but they did not show any subjective symptoms

The abnormal laboratory findings were improved soon after the MT-141 descontinuation.