Plant antibacterials: The challenges and opportunities.

Nature possesses an inexhaustible reservoir of agents that could serve as alternatives to combat the growing threat of antimicrobial resistance (AMR). While some of the most effective drugs for treating bacterial infections originate from natural sources, they have predominantly been derived from fungal and bacterial species. However, a substantial body of literature is available on the promising antibacterial properties of plant-derived compounds. In this comprehensive review, we address the major challenges associated with the discovery and development of plant-derived antimicrobial compounds, which have acted as obstacles preventing their clinical use. These challenges encompass limited sourcing, the risk of agent rediscovery, suboptimal drug metabolism, and pharmacokinetics (DMPK) properties, as well as a lack of knowledge regarding molecular targets and mechanisms of action, among other pertinent issues. Our review underscores the significance of these challenges and their implications in the quest for the discovery and development of effective plant-derived antimicrobial agents. Through a critical examination of the current state of research, we give valuable insights that will advance our understanding of these classes of compounds, offering potential solutions to the global crisis of AMR. © 2017 Elsevier Inc. All rights reserved.

Discovery, Synthesis, and Optimization of 1,2,4-Triazolyl Pyridines Targeting Mycobacterium tuberculosis.

The rise in multidrug resistant tuberculosis cases underscores the urgent need to develop new treatment strategies for tuberculosis. Herein, we report the discovery and synthesis of a new series of compounds containing a 3-thio-1,2,4-triazole moiety that show inhibition of Mycobacterium tuberculosis (Mtb) growth and survival. Structure-activity relationship studies led us to identify several potent analogs displaying low micromolar to nanomolar inhibitory activity, specifically against Mtb. The potent analogs demonstrated no cytotoxicity in mammalian cells at over 100 times the effective concentration required in Mtb and were bactericidal against Mtb during infection of macrophages. In the exploratory ADME investigations, we observed suboptimal ADME characteristics, which prompted us to identify potential metabolic liabilities for further optimization. Our preliminary investigations into the mechanism of action suggest that this series is not engaging the promiscuous targets that arise from many phenotypic screens. We selected for resistant mutants with the nanomolar potent nitro-containing compound 20 and identified resistant isolates with mutations in genes required for coenzyme F420 biosynthesis and the nitroreductase Ddn. This suggests that the aromatic nitro-1,2,4-triazolyl pyridines are activated by F420-dependent Ddn activity, similar to the nitro-containing TB drug pretomanid. We were able to circumvent the requirement for F420-dependent Ddn activity using compounds that contained non-nitro groups, identifying a key feature to be modified to avoid this predominant resistance mechanism. These studies provide the foundation for the development of a new class of 1,2,4-triazole compounds for the treatment of tuberculosis.

Identification of potential non-nucleoside MraY inhibitors for tuberculosis chemotherapy using structure-based virtual screening.

The efforts to limit the spread of the tuberculosis epidemic have been challenged by the rise of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. It is critical to discover new chemical scaffolds acting on novel or unexploited targets to beat this drug-resistant pathogen. MraY (phospho-MurNAc-pentapeptide translocase or translocase I) is an in vivo validated target for antibacterials-discovery. MraY is inhibited by nucleoside-based natural products that suffer from poor in vivo efficacy. The current study is focused on discovering novel chemical entities, particularly, non-nucleoside small molecules, as MraYMtb inhibitors possessing antituberculosis activity. In the absence of any reported X-ray crystal structures of MraYMtb, we used a homology model-based virtual screening approach combined with the ligand-based e-pharmacophore screening. We screened ∼12 million commercially available compounds from the ZINC15 database using GOLD software. The resulting hits were filtered using a 2-pronged screening method comprising e-pharmacophore hypotheses and docking against the MraYMtb homology model using Glide. Further clustering based on Glide scores and optimal binding interactions resulted in 15 in silico hits. We performed molecular dynamics (MD) simulations for the three best-ranking compounds and one other poorer-ranking compound, out of the 15 in silico hits, to analyze the interaction modes in detail. The MD simulations indicated stable interactions between the compounds and key residues in the MraY active site that are crucial for maintaining the enzymatic activity. These in silico hits could advance the antibacterial drug discovery campaign to find new MraY inhibitors for tuberculosis treatment.Communicated by Ramaswamy H. Sarma.

Plants-Derived Neuroprotective Agents: Cutting the Cycle of Cell Death through Multiple Mechanisms.

Neuroprotection is the preservation of the structure and function of neurons from insults arising from cellular injuries induced by a variety of agents or neurodegenerative diseases (NDs). The various NDs including Alzheimer's, Parkinson's, and Huntington's diseases as well as amyotropic lateral sclerosis affect millions of people around the world with the main risk factor being advancing age. Each of these diseases affects specific neurons and/or regions in the brain and involves characteristic pathological and molecular features. Hence, several in vitro and in vivo study models specific to each disease have been employed to study NDs with the aim of understanding their underlying mechanisms and identifying new therapeutic strategies. Of the most prevalent drug development efforts employed in the past few decades, mechanisms implicated in the accumulation of protein-based deposits, oxidative stress, neuroinflammation, and certain neurotransmitter deficits such as acetylcholine and dopamine have been scrutinized in great detail. In this review, we presented classical examples of plant-derived neuroprotective agents by highlighting their structural class and specific mechanisms of action. Many of these natural products that have shown therapeutic efficacies appear to be working through the above-mentioned key multiple mechanisms of action.