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Tackling Antibiotic Resistance with Compounds of Natural Origin: a Comprehensive Review

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Tackling Antibiotic Resistance with Compounds of Natural Origin: a Comprehensive Review 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. Leading causes of death in the world in 20162016 (blue(blue bars)bars) andand prognosisprognosis forfor antimicrobialantimicrobial resistanceresistance (AMR)(AMR) relatedrelated deathsdeaths inin 20502050 (red(red bar).bar). BacteriaThis problem use their is known genetic to plasticity scientists to and resist institutions attack by around antibiotics the throughworld, which mutations, are organizing acquisition to ofestablish genetic protocols material, to and address alteration the pr ofoblem the expression of antibiotic-resistant of their genome microbes. [3]. InProof this of way, this bacteriawas the 2012 that surviveChennai the Declaration attack of of an India, antibiotic in which become international the precursors experts of and the nextrepresentatives bacterial generations, of medical furtherentities aggravatingmet to draw theup problemaction plans of resistance. in the face Once of the antibiotic inexorable resistance advance genes of the are superbugs acquired, they[2]. Similar can be passedinitiatives from have one been bacterium promoted to another from private through and division public institutions processes or worldwide. by horizontal gene transfer [4]. HorizontalBacteria gene use transfertheir genetic processes plasticity can occurto resist by a transformation,ttack by antibiotics transduction through mutations, or conjugation acquisition with otherof genetic bacteria. material, These and mechanisms alteration of can the transfer expression antibiotic of their resistance genome to [3]. bacteria In this that way, have bacteria not been that subjectedsurvive the to antibioticattack of selectionan antibiotic pressure, become creating the prec reservoirsursors ofof resistantthe next bacteriabacterial in generations, the environment further [5]. Inaggravating addition, thethe epistasis problem of of the resistance. receptor bacteria Once antibiotic plays a fundamental resistance genes role in are the acquired, process of they acquisition can be ofpassed resistance from genes,one bacterium determining to another whether through these bacteria division are processes capable or of maintaining,by horizontal accumulating gene transferand [4]. propagatingHorizontal gene the genetictransfer material processes [6]. can occur by transformation, transduction or conjugation with otherAntibiotic bacteria. resistanceThese mechanisms is an example can oftransfer the enormous antibiotic capacity resistance for natural to bacteria evolution that andhave adaptation not been ofsubjected bacteria to to antibiotic different selection environments pressure, [7,8 creating]. Although reservoirs this process of resistant seems bacteria inevitable, in the humans environment have accelerated[5]. In addition, it through the epistasis various of anthropogenic the receptor ba activitiescteria plays [9,10 ].a fundamental The causes behindrole in thethe increaseprocess inof theacquisition number of of resistance antimicrobial-resistant genes, determining bacteria whether in recent these years bacteria include are the capable misuse ofof antibioticsmaintaining, in humansaccumulating and animals, and propagating inadequate the control genetic of material infections [6]. in hospitals and clinics or poor hygiene and sanitationAntibiotic [9–11 ].resistance In addition is toan the example causes mentioned,of the enormous the problem capacity worsens for natural as there isevolution a drought and in theadaptation discovery of ofbacteria new antibiotics. to different The environments increase in resistance [7,8]. Although rates in bacteria this process leads to seems a decrease inevitable, in the ehumansffectiveness have of accelerated existing antibiotics, it throug makingh various research anthropogenic in this field activities unattractive [9,10]. to The companies causes thatbehind decide the toincrease invest inin otherthe number types of of fields antimicrobial-resistant with greater chances bacteria of success in andrecent benefits years [ 12include,13]. This the concerningmisuse of trendantibiotics can be in observed humans inand Figure animals,2. inadequate control of infections in hospitals and clinics or poor hygieneIn view and sanitation of this scenario, [9–11]. In research addition on to alternative the causes ormentioned, complementary the problem therapies worsens to traditional as there is antibioticsa drought in has the emerged discovery strongly. of new Antimicrobial antibiotics. The products increase of in natural resistance origin rates have in beenbacteria positioned leads to as a compoundsdecrease in ofthe great effectiveness scientific interestof existing due toantibiotic their enormouss, making chemical research variety in this and field intrinsic unattractive properties to thatcompanies have promoted that decide their to studyinvest as in a other possible types therapeutic of fields with tool ingreater recent chances years. of success and benefits [12,13]. This concerning trend can be observed in Figure 2. Biomedicines 2020, 8, 405 3 of 30 Biomedicines 2020, 8, x FOR PEER REVIEW 3 of 32 FigureFigure 2. 2. ApproximateApproximate dates dates of discovery of discovery of new of classes new classes of antibiotics of antibiotics and identification and identification of bacterial of resistance.bacterial resistance. 2. Methodology In view of this scenario, research on alternative or complementary therapies to traditional antibioticsElectronic has emerged databases strongly. such as Antimicrobial PubMed, Scopus prod anducts ScienceDirect of natural origin were have used been to search positioned scientific as compoundscontributions of great until scientific September interest 2020, due using to their relevant enormous keywords. chemical Search variety terms and intrinsic included properties “natural thatantimicrobial”, have promoted “antimicrobial their study as resistance”, a possible therapeutic “polyphenols”, tool in “future recent years. medicine”, “natural origin”, “antibacterial compound”, “phytochemical” and their combinations. Literature focusing on the 2.antimicrobial
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