Ro 63-9141 is a new member of the pyrrolidinone-3-ylidenemethyl cephem series of cephalosporins. Its antibacterial spectrum was evaluated against significant gram-positive and gram-negative pathogens in comparison with those of reference drugs, including cefotaxime, cefepime, meropenem, and ciprofloxacin. Ro 63-9141 showed high antibacterial in vitro activity against gram-positive bacteria except ampicillin-resistant enterococci, particularly vancomycin-resistant strains of Enterococcus faecium. Its MIC at which 90% of the isolates tested were inhibited (MIC 90 ) for methicillin-resistant Staphylococcus aureus (MRSA) was 4 g/ml. Ro 63-9141 was bactericidal against MRSA. Development of resistance to the new compound in MRSA was not observed. Ro 63-9141 was more potent than cefotaxime against penicillin-resistant Streptococcus pneumoniae (MIC 90 ‫؍‬ 2 g/ml). It was active against ceftazidime-susceptible strains of Pseudomonas aeruginosa and against Enterobacteriaceae except Proteus vulgaris and some isolates producing extended-spectrum ␤-lactamases. The basis for the antibacterial spectrum of Ro 63-9141 lies in its affinity to essential penicillin-binding proteins, including PBP 2 of MRSA, and its stability towards ␤-lactamases. The in vivo findings were in accordance with the in vitro susceptibilities of the pathogens. These data suggest the potential utility of Ro 63-9141 for the therapy of infections caused by susceptible pathogens, including MRSA. Since insufficient solubility of Ro 63-9141 itself precludes parenteral administration in humans, a water-soluble prodrug, Ro 65-5788, is considered for development.Methicillin-resistant staphylococci (MRS) have become a serious problem in many parts of the world. Although the incidence of strains of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and other MRS varies from country to country and from hospital to hospital (3, 5), it has been steadily increasing worldwide in the last decade (10,18,19). MRS are resistant not only to the available ␤-lactam antibiotics, but also, in most instances, to structurally unrelated classes of antibacterials (for mainly unknown reasons) and thus represent a prime target in the current search for new antimicrobials.MRS are characterized by the expression of a special penicillin-binding protein (PBP), PBP 2Ј, that is not present in methicillin-susceptible staphylococci. 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-spe...

Small, hydrophilic molecules, including most important antibiotics in clinical use, cross the Gram-negative outer membrane through the water-filled channels provided by porins. We have determined the X-ray crystal structures of the principal general porins from three species of Enterobacteriaceae, namely Enterobacter aerogenes, Enterobacter cloacae, and Klebsiella pneumoniae, and determined their antibiotic permeabilities as well as those of the orthologues from Escherichia coli. Starting from the structure of the porins and molecules, we propose a physical mechanism underlying transport and condense it in a computationally efficient scoring function. The scoring function shows good agreement with in vitro penetration data and will enable the screening of virtual databases to identify molecules with optimal permeability through porins and help to guide the optimization of antibiotics with poor permeation.

No abstract

BAL30072 is a new monocyclic ␤-lactam antibiotic belonging to the sulfactams. Its spectrum of activity against significant Gram-negative pathogens with ␤-lactam-resistant phenotypes was evaluated and was compared with the activities of reference drugs, including aztreonam, ceftazidime, cefepime, meropenem, imipenem, and piperacillin-tazobactam. BAL30072 showed potent activity against multidrug-resistant (MDR) Pseudomonas aeruginosa and Acinetobacter sp. isolates, including many carbapenem-resistant strains. The MIC 90 s were 4 g/ml for MDR Acinetobacter spp. and 8 g/ml for MDR P. aeruginosa, whereas the MIC 90 of meropenem for the same sets of isolates was >32 g/ml. BAL30072 was bactericidal against both Acinetobacter spp. and P. aeruginosa, even against strains that produced metallo-␤-lactamases that conferred resistance to all other ␤-lactams tested, including aztreonam. It was also active against many species of MDR isolates of the Enterobacteriaceae family, including isolates that had a class A carbapenemase or a metallo-␤-lactamase. Unlike other monocyclic ␤-lactams, BAL30072 was found to trigger the spheroplasting and lysis of Escherichia coli rather than the formation of extensive filaments. The basis for this unusual property is its inhibition of the bifunctional penicillin-binding proteins PBP 1a and PBP 1b, in addition to its high affinity for PBP 3, which is the target of monobactams, such as aztreonam.

No abstract