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Summary: Background: The current pipeline for new antibiotics fails to fully address the significant threat posed by drug-resistant Gram-negative bacteria that have been identified by the World Health Organization (WHO) as a global health priority. New antibacterials acting through novel mechanisms of action are urgently needed. We aimed to identify new chemical entities (NCEs) with activity against Klebsiella pneumoniae and Acinetobacter baumannii that could be developed into a new treatment for drug-resistant infections. Methods: We developed a high-throughput phenotypic screen and selection cascade for generation of hit compounds active against multidrug-resistant (MDR) strains of K. pneumoniae and A. baumannii. We screened compound libraries selected from the proprietary collections of three pharmaceutical companies that had exited antibacterial drug discovery but continued to accumulate new compounds to their collection. Compounds from two out of three libraries were selected using “eNTRy rules” criteria associated with increased likelihood of intracellular accumulation in Escherichia coli. Findings: We identified 72 compounds with confirmed activity against K. pneumoniae and/or drug-resistant A. baumannii. Two new chemical series with activity against XDR A. baumannii were identified meeting our criteria of potency (EC50 ≤50 μM) and absence of cytotoxicity (HepG2 CC50 ≥100 μM and red blood cell lysis HC50 ≥100 μM). The activity of close analogues of the two chemical series was also determined against A. baumannii clinical isolates. Interpretation: This work provides proof of principle for the screening strategy developed to identify NCEs with antibacterial activity against multidrug-resistant critical priority pathogens such as K. pneumoniae and A. baumannii. The screening and hit selection cascade established here provide an excellent foundation for further screening of new compound libraries to identify high quality starting points for new antibacterial lead generation projects. Funding: BMBF and GARDP.

Abstract  Eggplant is one of the most common vegetable crops grown in India and other parts of the world. Leucinodes orbonalis is the key pest infesting eggplant, with international importance as it causes heavy damage in all eggplant growing areas. It is very difficult to control this pest since it feeds inside the shoot and fruit, and there is every possibility of toxic residues remaining in the fruits as they are harvested at frequent intervals and are consumed after little cooking. In the sub-himalayan region of West Bengal, India the pest was found to be most active during summer and the rainy season, particularly during May–August, and caused 49.5–81.0% damage to fruits. Peak infestation (81.0% fruit damage) was noticed in the first week of June (22nd standard week), when the mean temperature, mean relative humidity and weekly rainfall were 27.8°C, 79.2% and 81.2 mm respectively. The pest became less active during winter months particularly in December–January. Borer infestation showed a significant positive correlation (P = 0.05) with maximum and mean temperature, minimum and mean relative humidity and rainfall, whereas with maximum relative humidity the correlation was negative but non-significant. The insecticides evaluated in the field for L. orbonalis control on eggplant revealed that avermectin (Vertimec 1.9 EC; 0.5 ml/l) was the most effective in suppressing dead heart caused by the pest, closely followed by Beauveria bassiana (Biorin 107 conidia/ml; 1 ml/l) and Bacillus thuringiensis Berliner (Biolep 5 × 107 spores/ml; 1 g/l). Significantly lower levels of fruit damage were recorded after avermectin treatment, closely followed by DDVP (0.05%) (Nuvan 76 SL; 2 ml/3 l) when compared with the untreated control. The other insecticides tested, including a neem formulation (Neemactin 0.15 EC; 2.5 ml/l) and malathion (0.05%) (Malathion 50 EC; 1.0 ml/l), were less effective. None of the insecticides evaluated produced satisfactory results against L. orbonalis. However, avermectin, besides being environmentally safe, was effective for a longer duration and could thus be recommended for Integrated Pest Management programmes on eggplant. [ABSTRACT FROM AUTHOR]