Novel antibacterials acting on new targets are urgently needed to stay ahead of resistance. Phospho-MurNAc-pentapeptide translocase or MraY is an actively sought-after drug target for gram-positive and gram-negative bacteria and mycobacteria. MraY is a validated in vivo target that catalyzes one of the initial steps in peptidoglycan biosynthesis in bacterial cell walls, which is indispensable for bacterial viability. In this review, we provide an updated overview of the key binding interactions shared between all the known nucleoside natural products and an account of non-nucleoside or non-traditional MraY inhibitors. We also provide perspectives on opportunities that can be systematically addressed to develop clinically viable broad-spectrum or species-specific antibacterials targeting MraY.
Natural products have a long and rich history in drug discovery and development. Blockbuster drugs like aspirin and Taxol have been tremendously successful in the field of medicine, in improving human health. Traditional natural product-based drug discovery is based on observations of early in-vivo efficacies or potent cellular activities in phenotypic assays, without prior knowledge of a compound's mechanism of actions. In stark contrast, modern drug discovery utilizes a target-based approach, which allows for the design of small molecules to achieve target selectivity. However, this “one drug-one target” paradigm has shifted in recent years. It is now known that complex diseases (cancer, neurodegenerative diseases) are likely to require the modulation of multiple targets and/or signaling pathways (i.e., polypharmacology) for effective treatment. In this regard, natural products provide a unique opportunity for the discovery of multi-targeting drugs due to their privileged structures. Produced by biosynthetic pathways that require successive binding to various enzymes, natural product scaffolds have evolved to interact with multiple proteins, giving rise to a range of biological activities. While the polypharmacological nature of these remarkable small molecules are well established, the mechanisms in which they do so are less well-known. In this book chapter, using examples from the literature, we highlight several ways in which natural products can exhibit polypharmacology.
Targeting the early steps of the cell wall peptidoglycan biosynthesis by small molecules might lead to new bactericidal antibiotics. MurA catalyzes the first committed step in this highly conserved pathway and was validated as a target by the clinically used inhibitor fosfomycin. However, fosfomycin relies on irreversible binding to the catalytic cysteine residue in the MurA active site, which can be mutated to cause bacterial resistance against this drug. Since the early 2000s, research efforts were intensified to develop new inhibitors of MurA species. Numerous synthetic and natural compounds were identified by high-throughput wet screening of large chemical libraries or by in silico screening approaches. This review provides an overview of the currently known MurA inhibitors, the methods employed for hit finding, the mode of action and their antibacterial activity.
Microbial infections and the rise of antibiotic resistance pose a serious threat to public health. To combat bacterial infection and resistance, new bacterial targets and non-antibiotic treatment options must be identified. Recently, virulence factors have gained increasing attention as they play a crucial role in bacterial pathogenicity. As their inhibition does not kill the bacteria, the selection pressure for the emergence of new resistant mutants is reduced, while at the same time assisting the host immune system in eliminating the disarmed bacteria. Extracellular bacterial collagenases are the etiological hallmarks of many bacterial infections. They are metalloproteases characterized by their ability to digest the major scaffolds of the extracellular matrix, exposing deep tissues to bacteria and other toxins. As inhibition of virulence factors is considered a powerful non-traditional anti-infective strategy, in this review we summarize the recent advances in this field to combat antibiotic resistance. We focus on the virulence factor bacterial metalloproteases, their biological features, their identified substrates and small-molecule inhibitors.
MraY is a key enzyme in bacterial peptidoglycan biosynthesis. It is not addressed by any clinically used antibiotic, thus making it an attractive target for the development of novel antibacterial agents without cross resistance to established antimicrobial drugs. Several classes of uridine-derived natural products (“nucleoside antibiotics”) are known to inhibit MraY with remarkable activities. This review presents the most relevant sub-classes of nucleoside antibiotics and reported medicinal chemistry efforts to develop them towards antibacterial drug candidates. The following natural products and their analogues are discussed: (i) muraymycins; (ii) caprazamycins and related compounds; (iii) mureidomycins and related compounds; (iv) capuramycins; and (v) tunicamycins. Overall, we aim to demonstrate that it is perfectly feasible to treat naturally occurring nucleoside antibiotics as “hits” and to employ medicinal chemistry approaches for their structural optimization, even though their structural complexity might be associated with challenging synthetic work. Studies along this line might contribute to efforts towards the development of urgently needed new antibiotics.
Pseudomonas aeruginosa (PA) is an important hospital pathogen and new treatment options are urgently required. The pathoblocker or antivirulence approach is an attractive strategy towards novel anti-infectives with alternative modes-of-action. The disruption of bacterial cell-to-cell communication by inhibition of quorum sensing (QS) is one potential way to develop effective pathoblockers. This overview highlights recent advancements in the discovery of QS inhibitors against the pqs QS system of PA. This includes inhibitors interfering with the activity of the biosynthetic enzymes PqsA, PqsD, PqsE and PqsBC as well as the signal molecule receptor PqsR of the eponymous autoinducer molecule PQS. The review focuses on summarizing the main new structural classes for each target. Furthermore, in the conclusion the author gives a personal opinion on the most promising approaches and developments in this context.
Neuropathic pain, which affects 7–10% of the general population, is induced by the lesions or diseases of the somatosensory system including the central neurons and peripheral fibers. Numerous causes of neuropathic pain have been identified, and globally, its prevalence is rising continuously among the ever-increasing aging population, especially among those with diabetes and cancer. Most drugs approved for normal inflammatory pain (NSAIDs, etc.) are ineffective against CNS-related pain due to underlying mechanisms and pathways involved in initiating the neuropathy pain cascade. Hence, considering the multifactorial etiology of neuropathic pain, small molecule natural products (morphine onwards) and their synthetic variants have been explored against neuropathic pain, with remarkable success. However, the pharmacological liabilities (habit-forming, psychoactive, etc.) are still a major challenge with an ever-greater unmet need. The article presents a critical review of the types, manifestations, diagnosis, and different signaling pathways linked to the pharmacology of neuropathic pain and nociception. It summarizes diverse categories of natural products from medicinal plants like alkaloids, terpenoids, steroids, coumarins, glycosides, lignans and flavonoids revealing their pain attenuation abilities.
Pseudo-natural products (PNPs) combine natural product (NP) fragments in novel arrangements not accessible by current biosynthesis pathways. As such they can be regarded as non-biogenic fusions of NP-derived fragments. They inherit key biological characteristics of the guiding natural product, such as chemical and physiological properties, yet define small molecule chemotypes with unprecedented or unexpected bioactivity. We iterate the design principles underpinning PNP scaffolds and highlight their syntheses and biological investigations. We provide a cheminformatic analysis of PNP collections assessing their molecular properties and shape diversity. We propose and discuss how the iterative analysis of NP structure, design, synthesis, and biological evaluation of PNPs can be regarded as a human-driven branch of the evolution of natural products, that is, a chemical evolution of natural product structure.
