antibiotics Review Bacterial Resistance to Antimicrobial Agents Manuel F. Varela 1,* , Jerusha Stephen 2 , Manjusha Lekshmi 2, Manisha Ojha 1, Nicholas Wenzel 1, Leslie M. Sanford 1, Alberto J. Hernandez 1, Ammini Parvathi 3 and Sanath H. Kumar 2 1 Department of Biology, Eastern New Mexico University, Portales, NM 88130, USA; [email protected] (M.O.); [email protected] (N.W.); [email protected] (L.M.S.); [email protected] (A.J.H.) 2 Post-Harvest Technology, ICAR-Central Institute of Fisheries Education, Seven Bungalows, Andheri (W), Mumbai 400061, India; [email protected] (J.S.); [email protected] (M.L.); [email protected] (S.H.K.) 3 CSIR-National Institute of Oceanography, Regional Centre, Kochi 682018, India; [email protected] * Correspondence: [email protected] Abstract: Bacterial pathogens as causative agents of infection constitute an alarming concern in the public health sector. In particular, bacteria with resistance to multiple antimicrobial agents can confound chemotherapeutic efficacy towards infectious diseases. Multidrug-resistant bacteria harbor various molecular and cellular mechanisms for antimicrobial resistance. These antimicrobial resistance mechanisms include active antimicrobial efflux, reduced drug entry into cells of pathogens, enzymatic metabolism of antimicrobial agents to inactive products, biofilm formation, altered drug targets, and protection of antimicrobial targets. These microbial systems represent suitable focuses for investigation to establish the means for their circumvention and to reestablish therapeutic effec- tiveness. This review briefly summarizes the various antimicrobial resistance mechanisms that are harbored within infectious bacteria. Citation: Varela, M.F.; Stephen, J.; Lekshmi, M.; Ojha, M.; Wenzel, N.; Keywords: bacteria; antimicrobial resistance; infection; pathogenesis; multidrug resistance Sanford, L.M.; Hernandez, A.J.; Parvathi, A.; Kumar, S.H. Bacterial Resistance to Antimicrobial Agents. Antibiotics 2021, 10, 593. https:// 1. Introduction doi.org/10.3390/antibiotics10050593 Bacteria as microbial pathogens are causative agents of life-threatening infectious dis- eases [1]. Such pathogenic bacteria produce alarming numbers in terms of morbidity and Academic Editor: Nahed El-Najjar mortality outcomes [2,3]. One crucial avenue towards bacterial pathogenesis involves the reduction in the therapeutic effects of antibacterial chemotherapy [4,5]. Throughout their Received: 22 April 2021 evolutionary history, bacterial pathogens have developed various means of resisting the Accepted: 14 May 2021 Published: 17 May 2021 inhibitory and bactericidal consequences of antimicrobial agents [4]. Such antimicrobial resistance systems involve the engagement of bacterial molecular and cellular-based ma- Publisher’s Note: MDPI stays neutral chinery [6]. Interestingly, the selection of a bacterial variant with resistance to a single with regard to jurisdictional claims in antimicrobial agent frequently manifests the emergence of a multidrug resistance character- published maps and institutional affil- istic in the new mutant [7]. Newly emerged bacterial pathogens with resistance to multiple iations. antibacterial agents can result in compromised efficacy in the treatment of infection [3,8]. Mechanisms of antimicrobial resistance include the active export systems within the membranes of bacteria, prevention of antimicrobial entrance into cells of pathogenic bacteria, enzymatic destruction of antimicrobial agents, production of thick biofilms, modified tar- gets of antimicrobials, and bacterial sites of action that are protected from antimicrobials, Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. (Figure1) [2,4]. Furthermore, multidrug-resistant bacteria have developed mechanisms that This article is an open access article confer the DNA transfer of genetic determinants of resistance to pathogenic species in the distributed under the terms and clinical setting, the food production industry, the human gut, and in agriculture [9]. conditions of the Creative Commons Thus, new strategies for the circumvention of bacterial resistance to antimicrobial Attribution (CC BY) license (https:// agents are desired [10]. In order to discover novel approaches to address multiple an- creativecommons.org/licenses/by/ timicrobial resistances in these microbial pathogens, however, it is necessary to attain 4.0/). a clear understanding of these resistance systems at the molecular and cellular levels. Antibiotics 2021, 10, 593. https://doi.org/10.3390/antibiotics10050593 https://www.mdpi.com/journal/antibiotics Antibiotics 2021, 10, 593 2 of 22 Antibiotics 2021, 10, x FOR PEER REVIEW For young and new investigators, here, we consider an introductory overview2 of 22 of each of these disparate bacterial resistance mechanisms here. Figure 1. BacterialFigure mechanisms 1. Bacterial of mechanisms resistance toof antimicrobialresistance to antimicrobial agents. The commonagents. The mechanisms common mechanisms of antibiotic of resistance antibiotic resistance in bacteria are enzymatic hydrolysis (1), enzymatic modifications of antibiot- in bacteria are enzymatic hydrolysis (1), enzymatic modifications of antibiotics by group transfer and redox process (2), ics by group transfer and redox process (2), modifications of antibiotic targets (3), reduced perme- modifications of antibiotic targets (3), reduced permeability to antibiotics by modifications of porins (4), and active extrusion ability to antibiotics by modifications of porins (4), and active extrusion of antibiotics by mem- of antibiotics bybrane membrane efflux pumps efflux pumps (5). (5). Thus, new2. Enzyme-Based strategies for Antimicrobial-Inactivationthe circumvention of bacterial Systems resistance to antimicrobial agents are desired [10]. In order to discover novel approaches to address multiple antimi- Along the timeline of antibiotic discovery and introduction, several enzymatic mecha- crobial resistances in these microbial pathogens, however, it is necessary to attain a clear nisms of antibiotic inactivation were also discovered. Although very few novel mechanisms understanding of these resistance systems at the molecular and cellular levels. For young of antibiotic resistance have been reported in recent times, several new variants of known and new investigators, here, we consider an introductory overview of each of these dis- enzymes that endow bacteria with resistance to newly introduced drugs have emerged, parate bacterial resistance mechanisms here. suggesting that the bacterial response to new antibiotics or the modified versions of existing antibiotics is swift. The enzymatic mechanisms of antibiotic resistance include hydroly- 2. Enzyme-Based Antimicrobial-Inactivation Systems sis, group transfer, and redox processes [4]. In terms of diversity, evolution, and spread, Along theantibiotic timeline resistance of antibiotic enzymes discovery contribute and introduction, remarkably several to the bacterialenzymatic ability mech- to overcome anisms of antibioticantibiotic inactivation pressure. The wereβ-lactamases also discovered. are the Although oldest known very and few the novel most mecha- diverse antibiotic nisms of antibioticdegrading resistance enzymes have that been cleave reported the β in-lactam recent ringtimes, of several the penicillin new variants group of antibiotics known enzymesand render that endow them ineffective.bacteria with The resistance first such toβ -lactamasenewly introdu wasced discovered drugs have soon after the emerged, suggestingfirst antibiotic that penicillinthe bacterial was response in clinical to use.new Scientificantibiotics evidence or the modified suggests thever- existence of sions of existingβ-lactamases antibiotics before is swift. penicillin The enzymatic was clinically mechanisms employed, of emphasizing antibiotic resistance that the production include hydrolysis,of antimicrobial group transfer, compounds and redox and the processes mechanisms [4]. In to terms endure of themdiversity, occur evolu- in parallel in the tion, and spread,environment antibiotic [11 resistance]. Bacteria enzymes that produce contribute antibiotics remarkably apparently to the bacterial require abil- mechanisms to ity to overcomeovercome antibiotic the lethalpressure. effects The ofβ- thelactamases compounds, are the and oldest these known are in and the the form most of concurrent diverse antibioticproduction degrading of degradative enzymes that enzymes, cleave mutations the β-lactam in targets ring of of the antibiotics, penicillin or group active extrusion of antibioticsof and antibiotics render them from ineffective. the cell so The that first the such antibiotic-producing β-lactamase was celldiscovered is protected. soon However, after the firstthe antibiotic selection penicillin pressure createdwas in dueclinical to the use. extensive Scientific use evidence of antibiotics suggests in humans the ex- and animals istence of β-lactamases before penicillin was clinically employed, emphasizing that the production of antimicrobial compounds and the mechanisms to endure them occur in parallel in the environment [11]. Bacteria that produce antibiotics apparently require mechanisms to overcome the lethal effects of the compounds, and these are in the form of Antibiotics 2021, 10, 593 3 of 22 propagated the resistant clones of bacteria in clinical and food production environments. In due course of time, genetic exchange mechanisms facilitated the wider dissemination