Secondary Metabolites and Peptides as Unique Natural Reservoirs of New Therapeutic Leads for Treatment of Cancer and Microbial Infections

The bleakest outlook for a "post-antibiotic era" is one in which microbial infections can no longer be cured. The traditional antibiotic pipeline has been exhausted, while antimicrobial resistance has become a multifaceted crisis, imposing a serious threat to human health with more than 700,000 deaths each year globally. Furthermore, in line with the latest reports from the World Health Organisation (WHO), this number is expected to grow up to 10-fold by 2050, meaning that infectious diseases will be the principal cause of mortality rather than cancer (1). The growing ineffectiveness of clinically used antibiotics could result in new pandemics that will be difficult to stem without effective replacement drugs. The current SARS-CoV-2 crisis is illuminating with respect to the consequences of being poorly armed to combat infection, and how this impacts all aspects of modern society; medical, social, and economic. From this scenario, it is clear how the discovery of new antimicrobial treatments is highly demanded.Inspired by nature, antimicrobial peptides (AMPs) and secondary metabolites (SM) are gaining attention for their clinical translation and remain the best storehouse for leads in modern drug discovery. AMPs are evolutionarily conserved elements of the innate immune system of almost all living organisms and have distinct advantages compared to conventional antibiotics. Indeed, they have a large spectrum of antimicrobial activity and cause cell disruption through a non-specific mechanism based on the perturbation of the target microbial cell membrane, thus making microbes less prone to acquire resistance to them (2). AMPs also display additional functions that indirectly promote the clearance of microorganisms through the modulation of inflammatory host responses and the promotion of wound healing. In addition, some of them have promising anticancer properties. However, some inherent drawbacks of AMPs need to be overcome for their clinical translation. Among them, the short half-life owing to the susceptibility to protease degradation; the inactivity at physiological salt concentrations; the cytotoxicity towards host cells, and the limited targeted delivery. Currently, most of the AMPs under clinical evaluation are positively charged derivatives of naturally occurring AMPs and are limited to topical administration for an effective concentration at the target site (3).Plants are a unique source of medicines and traditional remedies since ancient times. Due to their biodiversity, medicinal plants represent the largest library of structurally diverse SM that has ever existed and cannot be matched by any synthetic screening libraries. Several clinically-used therapeutic agents with antimicrobial and/or antitumor activity derive from SM by means of chemical transformations or total syntheses, thus strengthening the pivotal role of nature as a source of hit and lead compounds in drug discovery (4)(5)(6).In this Research Topic, we present a collection of original research and review articles that show the ability of phytochemicals and natural peptides to display in vitro/in vivo activities against tumour cells and/or microbial pathogens and how the employment of computational techniques and/or efficient synthetic tools and nanotechnology approaches offer promising solutions for the improvement of traditional medicine and the production of proper drug-delivery systems. Finally, the minireview of Caimano et al. investigated the possibility to increase the dissolution and stability of several inhibitors of the Hedgehog (HH) pathway, whose pharmacological blockade is a promising approach for the clinical management of Medulloblastoma (MB), a highly aggressive paediatric tumour of the cerebellum. The poor pharmacological properties and the low capability to cross the blood-brain barrier of HH inhibitors represents one of the main challenges for treatment of MB. The authors have reported several formulation strategies to improve the bioavailability of the HH inhibitor GlaB, an isoflavone naturally found in the seeds of Derris glabrescens, and that is currently patent protected and under preclinical phase for treatment of different HH-dependent cancers.