In Vitro Activities of Novel trans -3,5-Disubstituted Pyrrolidinylthio-1β-Methylcarbapenems with Potent Activities against Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa

Abstract

The in vitro activities of the novel 1␤-methylcarbapenems J-111,225, J-114,870, and J-114,871, which have a structurally unique side chain that consists of a trans-3,5-disubstituted 5-arylpyrrolidin-3-ylthio moiety at the C-2 position, were compared with those of reference antibiotics. Among isolates of both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS), 90% were inhibited by J-111,347 (prototype), J-111,225, J-114,870, and J-114,871 at concentrations of 2, 4, 4, and 4 g/ml (MICs at which 90% of isolates are inhibited [MIC 90 s]), respectively, indicating that these agents were 32-to 64-fold more potent than imipenem, which has an MIC 90 of 128 g/ml. Although these drugs were less active in vitro than vancomycin, which had MIC 90 s of 1 and 2 g/ml for MRSA and MRCoNS, respectively, the new carbapenems displayed better killing kinetics than vancomycin. The potent anti-MRSA activity was ascribed to the excellent affinities of the new carbapenems for penicillin-binding protein 2a of MRSA. Since the new carbapenems also exhibited good activity against gram-positive and -negative bacteria including clinically important pathogens such as penicillin-resistant Streptococcus pneumoniae, Haemophilus influenzae, members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Clostridium difficile, as well as MRSA, the novel carbapenems are worthy of further evaluation.The emergence of multidrug-resistant microorganisms has caused serious concern about infectious diseases worldwide. Although more than three decades have passed since the first report of methicillin-resistant Staphylococcus aureus (MRSA), MRSA still presents a serious problem worldwide as a cause of nosocomial infections (7, 12). Vancomycin, a cyclic glycopeptide antibiotic, has been extensively used in the clinic to treat MRSA infections. However, it is not an ideal antibiotic because of the slow clinical response (6) and potential adverse effects (3). Furthermore, the emergence of MRSA strains with reduced susceptibility to vancomycin accelerated an urgent need for new chemotherapeutic agents for the treatment of MRSA infections (5).Previously reported ␤-lactam antibiotics with activity against methicillin-resistant staphylococci (MRS) such as L-695,256 (2), SM-17466 (13), BO-3482 (8), TOC-39 (4), MC-02,479/ RWJ-54428 (F. Malouin, C. Chan, S. Bond, S. Chamberland, and V. J. Lee, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-177, p. 176, 1997), Ro 63-9141 (P. Hohl, P. Angehrn, R. L. Then, P. Hebeisen, and I. Heinze-Krauss, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-24, p. 239, 1998), and L-786,392 (J. Huber, K. L. Dorso, J. Koheler, H. Kropp, H. Rosen, and L. L. Silver, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-30, p. 240, 1998) all had weak activities against gram-negative organisms and/or a lack of antipseudomonal activity.In the course of our derivatization study of 1␤-methylcarbapenems, a novel trans-3,5-...

In Vitro and In Vivo Activities of Novel 2-(Thiazol-2-ylthio)-1β-Methylcarbapenems with Potent Activities against Multiresistant Gram-Positive Bacteria

“…As an approach to combat these resistant pathogens, chemical modifications of ␤-lactams targeting the resistance mechanism have been conceived, and to date, a number of reports have appeared that describe new ␤-lactams with improved activity against MRSA. These include different classes of ␤-lactams, especially cephalosporins and carbapenems (1,2,8,11,16,19,25). However, no agent has shown a measurable advantage over others in the late stages of clinical development.…”

In Vitro and In Vivo Properties of Ro 63-9141, a Novel Broad-Spectrum Cephalosporin with Activity against Methicillin-Resistant Staphylococci

“…However, the intensive search for new antistaphylococcal drugs has shown recently (1,7,11,12,14) that it is possible to achieve strong inhibition of PBP 2Ј with selected ␤-lactam structures. Ro 63-9141 is a member of the class of pyrrolidinone-3-ylidenemethyl cephems, which show high potency against PBP 2Ј of S. aureus but higher IC 50 s against normal, sensitive PBPs than other ␤-lactam antibiotics, e.g., methicillin and imipenem.…”

“…This PBP is causally connected with methicillin resistance, as it functions as a transpeptidase and is not efficiently inhibited by commercially available ␤-lactams, in contrast to the other transpeptidases in staphylococci, PBP 1, PBP 2, and PBP 3. However, the poor affinity of PBP 2Ј for ␤-lactam antibiotics does not seem to be inherent in the ␤-lactam structure since new carbapenems and cephalosporins that are good inhibitors of PBP 2Ј have recently been described (1,6,11,12,14,20).Ro 63-9141, the active principle of the water-soluble prodrug Ro 65-5788, is a novel parenteral cephalosporin with broad-spectrum activity against gram-positive and gram-negative pathogens. It differs from older, broad-spectrum cephalosporins in that it has antibacterial activity against MRS isolates.…”

Sulfonamide-1,2,4-thiadiazole Derivatives as Antifungal and Antibacterial Agents: Synthesis, Biological Evaluation, Lipophilicity, and Conformational Studies

“…[2][3][4][5][6] With the increase in resistance of bacteria to antibiotic treatment, attention was given on developing novel approaches to antimicrobial therapy. [7][8][9][10][11][12][13] We have previously reported the significant antifungal activity of a series of sulfonamide-1,2,4-triazole derivatives against a series of micromycetes, compared to the commercial fungicide bifonazole. These compounds have also shown a comparable bactericidal effect to that of streptomycin but better activity than chlorampenicol respectively against various bacteria.…”