ME-1071

ME1071, a maleic acid derivative, is a novel, specific inhibitor of metallo-β-lactamases (MBLs). In vitro, ME1071 can potentiate the activity of carbapenems against MBL-producing Pseudomonas aeruginosa. To confirm the clinical efficacy of ME1071 in ventilator-associated pneumonia (VAP) caused by MBL-producing P. aeruginosa, a mouse model that mimics VAP by placement of a plastic tube in the bronchus was used. Biapenem (100 mg/kg) or ME1071 plus biapenem (each 100 mg/kg) was administered intraperitoneally every 12 h beginning at 12 h after inoculation. Survival was evaluated over 7 days. At 30 h post infection, mice were sacrificed and the numbers of viable bacteria in the lungs and bronchoalveolar lavage fluid (BALF) were compared. Histopathological analysis of lung specimens was also performed. The pharmacokinetics of ME1071 was analysed after initial treatment. The ME1071 plus biapenem combination group displayed significantly longer survival compared with the control and biapenem monotherapy groups (P<0.05). Furthermore, the number of viable bacteria in the lungs was significantly lower in the combination group (P<0.05). Histopathological examination of lung specimens indicated that progression of lung inflammation was prevented in the combination group. Furthermore, total cell and neutrophil counts, as well as cytokine levels, in BALF were significantly decreased (P<0.05) in the combination group. The percentage time above the MIC (%T>MIC) for biapenem without ME1071 was 0% in plasma; however, this value was elevated to 10.8% with ME1071. These results suggest that ME1071 is potent and effective for treatment of VAP caused by MBL-producing P. aeruginosa.

To obtain a status of a medicinal product, a compound possessing potential antimicrobial activity and displaying no cytotoxicity, must undergo three phases of clinical trials to prove its therapeutic efficacy, safety and quality. Properties of the compound should be based on the results of studies meeting specific criteria. Studies should be: randomized, double-blind, involving sufficient number of volunteers, concerning the infections localized in strictly defined area and caused by identified microorganisms. After the medicinal product is authorized to be on the market, clinical trials of the fourth phase are carried out to detect adverse effects, overdose symptoms, interactions of the new drug with other medicinal products and to establish characteristic of activity among groups such as children, elderly, women in pregnancy and patients suffering from other diseases, but only if the benefits of receiving treatment outweigh the risks. This article is a second part of the series associated with searching for new antibacterial agents and it relates to performance of clinical trials and the new compounds belonging to the class of beta-lactams. Among the 9 presented compounds, candidates to become medicinal products, two belong to the cephalosporins (CXA-101, S-649266), one to carbapenems (razupenem), three to monobactams (BAL30072, BAL30376, MC-1) and three to beta-lactamase inhibitors (NXL-104, MK-7655, ME1071).