biomedicines Review Tackling Antibiotic Resistance with Compounds of Natural Origin: A Comprehensive Review Francisco Javier Álvarez-Martínez 1 , Enrique Barrajón-Catalán 1,* and Vicente Micol 1,2 1 Institute of Research, Development and Innovation in Health Biotechnology of Elche (IDiBE), Universitas Miguel Hernández (UMH), 03202 Elche, Spain; [email protected] (F.J.Á.-M.); [email protected] (V.M.) 2 CIBER, Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud Carlos III (CB12/03/30038), 28220 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-965222586 Received: 18 September 2020; Accepted: 9 October 2020; Published: 11 October 2020 Abstract: Drug-resistant bacteria pose a serious threat to human health worldwide. Current antibiotics are losing efficacy and new antimicrobial agents are urgently needed. Living organisms are an invaluable source of antimicrobial compounds. The antimicrobial activity of the most representative natural products of animal, bacterial, fungal and plant origin are reviewed in this paper. Their activity against drug-resistant bacteria, their mechanisms of action, the possible development of resistance against them, their role in current medicine and their future perspectives are discussed. Electronic databases such as PubMed, Scopus and ScienceDirect were used to search scientific contributions until September 2020, using relevant keywords. Natural compounds of heterogeneous origins have been shown to possess antimicrobial capabilities, including against antibiotic-resistant bacteria. The most commonly found mechanisms of antimicrobial action are related to protein biosynthesis and alteration of cell walls and membranes. Various natural compounds, especially phytochemicals, have shown synergistic capacity with antibiotics. There is little literature on the development of specific resistance mechanisms against natural antimicrobial compounds. New technologies such as -omics, network pharmacology and informatics have the potential to identify and characterize new natural antimicrobial compounds in the future. This knowledge may be useful for the development of future therapeutic strategies. Keywords: natural antimicrobial; antimicrobial resistance; polyphenols; future medicine; natural origin; antibacterial compound; phytochemicals 1. Introduction Antimicrobial resistance (AMR) and the inexorable advance of superbacteria poses a great threat to human health worldwide. If this problem is not tackled, the antibiotics we have used with great success so far could become substances unable to help us against infections caused by bacteria, going back to a worrying pre-antibiotic era. According to data from the United Kingdom government [1], 10 million deaths could happen annually due to antibiotic resistance by 2050, becoming one of the leading causes of death in the world (Figure1). This problem is known to scientists and institutions around the world, which are organizing to establish protocols to address the problem of antibiotic-resistant microbes. Proof of this was the 2012 Chennai Declaration of India, in which international experts and representatives of medical entities met to draw up action plans in the face of the inexorable advance of the superbugs [2]. Similar initiatives have been promoted from private and public institutions worldwide. Biomedicines 2020, 8, 405; doi:10.3390/biomedicines8100405 www.mdpi.com/journal/biomedicines Biomedicines 2020, 8, 405 2 of 30 Biomedicines 2020, 8, x FOR PEER REVIEW 2 of 32 Figure 1.1. 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