antibiotics Review Phytochemicals: A Promising Weapon in the Arsenal against Antibiotic-Resistant Bacteria Bahman Khameneh 1 , N. A. Michael Eskin 2 , Milad Iranshahy 3, * and Bibi Sedigheh Fazly Bazzaz 1,4, *   Citation: Khameneh, B.; Eskin, N.A.M.; Iranshahy, M.; Fazly Bazzaz, B.S. Phytochemicals: A Promising Weapon in the Arsenal against Antibiotic-Resistant Bacteria. Antibiotics 2021, 10, 1044. https:// doi.org/10.3390/antibiotics10091044 Academic Editor: Filippo Maggi Received: 20 July 2021 Accepted: 17 August 2021 Published: 26 August 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Pharmaceutical Control, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 9177948954, Iran; khamenehbagherib@mums.ac.ir 2 Department of Food and Human Nutritional Sciences, Faculty of Agricultural and Food Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada; michael.eskin@umanitoba.ca 3 Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 9177948954, Iran 4 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948954, Iran * Correspondence: IranshahiMl@mums.ac.ir (M.I.); Fazlis@mums.ac.ir (B.S.F.B.); Tel.: +98-51-31801253 (M.I.); +98-51-31801130 (B.S.F.B.); Fax: +98-51-38823251 (M.I. & B.S.F.B.) Abstract: The extensive usage of antibiotics and the rapid emergence of antimicrobial-resistant mi- crobes (AMR) are becoming important global public health issues. Many solutions to these problems have been proposed, including developing alternative compounds with antimicrobial activities, man- aging existing antimicrobials, and rapidly detecting AMR pathogens. Among all of them, employing alternative compounds such as phytochemicals alone or in combination with other antibacterial agents appears to be both an effective and safe strategy for battling against these pathogens. The present review summarizes the scientific evidence on the biochemical, pharmacological, and clin- ical aspects of phytochemicals used to treat microbial pathogenesis. A wide range of commercial products are currently available on the market. Their well-documented clinical efficacy suggests that phytomedicines are valuable sources of new types of antimicrobial agents for future use. Innovative approaches and methodologies for identifying plant-derived products effective against AMR are also proposed in this review. Keywords: phytochemicals; antibiotic resistance; complementary medicine; herbal medicine; clini- cal applications 1. Introduction According to various surveys, there is a direct relationship between the increased use of antibiotics and the creation of resistant bacteria. The appearance of resistant microorgan- isms to drugs leads to the currently available treatment regimes becoming less effective or totally ineffective [1–4]. As a result, this has become a prominent issue and a serious concern for global health agencies such as the World Health Organization, Centers for Disease Control, and regional health ministries. Additionally, it represents a challenging problem for the medical fraternity [5,6]. In addition, the effectiveness of antibiotics has been substantially reduced by the existence of different resistance mechanisms. Of these, the major reasons are antibiotic inactivation by enzyme production, alteration of drug targets, changes in cell permeability, the intrinsic expression of efflux pumps, and biofilm formation. The last one, in particular, acts as a defense against drugs and contributes to the sustained persistence of resistant bacteria. The first antibiotic, penicillin, was discovered by Alexander Fleming in 1928. Since then, other β-lactam antibiotics identified include cephalosporins, carbapenems, and monobactams. They all contain a four-membered cyclic ring consisting of three carbon atoms and one nitrogen atom. The nitrogen atom is attached to the β-carbon relative to the carbonyl group, and hence the name β-lactam is used. Antibiotics 2021, 10, 1044. https://doi.org/10.3390/antibiotics10091044 https://www.mdpi.com/journal/antibiotics