Gramicidin S identified as a potent inhibitor for cytochrome bd-type quinol oxidase

AbstractGramicidin S, a cationic cyclic decapeptide, exhibits the potent antibiotic activity through perturbation of lipid bilayers of the bacterial membrane. From the screening of natural antibiotics, we identified gramicidin S as a potent inhibitor for cytochrome bd-type quinol oxidase from Escherichia coli. We found that gramicidin S inhibited the oxidase with IC50 of 3.5μM by decreasing Vmax and the affinity for substrates but showed the stimulatory effect at low concentrations. Our findings would provide a new insight into the development of gramicidin S analogs, which do not share the target and mechanism with conventional antibiotics

Beauvericin counteracted multi-drug resistant Candida albicans by blocking ABC transporters

AbstractMulti-drug resistance of pathogenic microorganisms is becoming a serious threat, particularly to immunocompromised populations. The high mortality of systematic fungal infections necessitates novel antifungal drugs and therapies. Unfortunately, with traditional drug discovery approaches, only echinocandins was approved by FDA as a new class of antifungals in the past two decades. Drug efflux is one of the major contributors to multi-drug resistance, the modulator of drug efflux pumps is considered as one of the keys to conquer multi-drug resistance. In this study, we combined structure-based virtual screening and whole-cell based mechanism study, identified a natural product, beauvericin (BEA) as a drug efflux pump modulator, which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette (ABC) transporters; meantime, BEA alone has fungicidal activity in vitro by elevating intracellular calcium and reactive oxygen species (ROS). It was further demonstrated by histopathological study that BEA synergizes with a sub-therapeutic dose of ketoconazole (KTC) and could cure the murine model of disseminated candidiasis. Toxicity evaluation of BEA, including acute toxicity test, Ames test, and hERG (human ether-à-go-go-related gene) test promised that BEA can be harnessed for treatment of candidiasis, especially the candidiasis caused by ABC overexpressed multi-drug resistant C. albicans

Ivermectin and malaria control

Abstract As the world begins to realize the very real prospect of eliminating malaria as a public health problem globally, the scientific community is acutely aware that novel and innovative new tools will be required if that lofty goal is to be accomplished. Moreover, the need for comprehensive, integrated products and interventions is being recognized in order for the critical ‘final steps’ toward elimination to be taken successfully. Failure to take these crucial last steps have dogged all past global disease elimination programmes, except for smallpox. The success of ivermectin in driving two of the most devastating and disfiguring neglected tropical diseases (NTD) to the brink of elimination has been well documented. The drug also bestows immeasurable non-target benefits, increasing the health and socioeconomic prospects of all communities where mass drug administration (MDA) has been carried out. Ivermectin kills a variety of parasites and insects, including the Anopheline vectors of malaria parasites. In view of long-standing MDA programmes, increasing attention is now being paid to the potential offered by re-formulating and re-purposing ivermectin to function as a feed-though mosquitocidal tool. This will provide a comprehensively beneficial weapon, for the anti-malarial armamentarium, as well as for probably improving the impact on existing target diseases. Prospects currently look highly promising, especially as the drug is already proven to be extremely safe for human use. However, for maximum impact, detailed analysis of various analogues of the unique ivermectin, as well as the parent avermectin compounds, will need to be undertaken. ‘Ivermectin’ comprises an imprecise mix of two compounds, both of which are potent anthelmintics. Yet recently, it has been confirmed that only the minor of the two component compounds is molluscicidal. Further structure activity relationship studies may well identify the analogue, analogues or combination thereof best suited for use in a concerted initiative to simultaneously tackle malaria and other NTD in poly-parasitized communities

Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization

By emulating the universal biosynthetic strategy, which employs modular assembly and divergent cyclizations, we have developed a four-step synthetic process to yield a collection of natural-product-inspired scaffolds. Modular assembly of building blocks onto a piperidine-based manifold 6, having a carboxylic acid group, was achieved through Ugi condensation, N-acetoacetylation and diazotransfer, leading to cyclization precursors. The rhodium-catalyzed tandem cyclization and divergent cycloaddition gave rise to tetracyclic and hexacyclic scaffolds by the appropriate choice of dipolarophiles installed at modules 3 and 4. A different piperidine-based manifold 15 bearing an amino group was successfully applied to demonstrate the flexibility and scope of the unified four-step process for the generation of structural diversity in the fused scaffolds. Evaluation of in vitro antitrypanosomal activities of the collections and preliminary structure-activity relationship (SAR) studies were also undertaken

In Situ Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor

In situ click chemistry is a target-guided synthesis approach for discovering novel lead compounds by assembling organic azides and alkynes into triazoles inside the affinity site of target biogenic molecules such as proteins. We report in situ click chemistry screening with human D-amino acid oxidase (hDAO), which led to the identification of a more potent hDAO inhibitor. The hDAO inhibitors have chemotherapeutic potential as antipsychotic agents. The new inhibitor displayed competitive inhibition of hDAO and showed significantly increased inhibitory activity against hDAO compared with that of an anchor molecule of in situ click chemistry