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-...