Bacterial Resistance to Antimicrobial Agents

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 effectiveness. This review briefly summarizes the various antimicrobial resistance mechanisms that are harbored within infectious bacteria.

Keywords: antimicrobial resistance; bacteria; infection; multidrug resistance; pathogenesis.

Figure 1

Bacterial mechanisms of resistance to antimicrobial agents. The common mechanisms of antibiotic resistance in bacteria are enzymatic hydrolysis (1), enzymatic modifications of antibiotics by group transfer and redox process (2), modifications of antibiotic targets (3), reduced permeability to antibiotics by modifications of porins (4), and active extrusion of antibiotics by membrane efflux pumps (5).

Figure 2

Evolution of β-lactamases. Within five decades of discovering the first penicillin-degrading enzyme, β-lactamases capable of hydrolyzing most β-lactam antibiotics, and resistance to inhibitors have emerged. The ability to tolerate a broad spectrum of β-lactams and inhibitor combinations is bolstered by the presence of multiple β-lactamase-encoding genes in a single pathogen.

Figure 3

Penicillin and penicillin-binding protein of the bacterial cell wall. (1) The peptidoglycan layer of a bacterial cell wall harbors the repeating moieties of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). The NAM subunits bind short variable peptide chains, usually l-Ala and two distal d-Ala residues. (2) The PBP cross-links the peptide side chain, releasing a free Ala. (3) Upon cross-linking, the PBP dissociates from the cell wall. (4) Penicillin binds the PBP active site, affecting its enzyme activity. (5) The β-lactam ring of penicillin is cleaved during its reaction with PBP. Penicillin stays covalently bound PBP, permanently inhibiting the active site. Altered PBPs, such as PBP2a, are unable to accommodate penicillin-binding, preventing cell wall synthesis inhibition [48,49].

Figure 4

Types of antimicrobial target protection mechanisms. (I) The target protection protein (TPP) directly displaces the antimicrobial agent from its active site on the target, preventing antimicrobial action. (II) The target protection protein binds an allosteric site of the target, which induces a conformation change and the dissociation of the antimicrobial agent from the target site. (III) The target protection protein induces a global conformational change to reestablish target function despite the formation of a target-drug complex [84]. This figure kindly provided courtesy of Ann F. Varela.

Figure 5

Crystal structure of bacterial ABC efflux pump from S. aureus. The top portion of the ABC transporter Sav1866 is depicted in blue and light blue and represents the two TMDs (sometimes called membrane-spanning domains, MSDs) of the protein, while the orange and red colors depict the two NBDs [104]. The model structure was generated using NGL Viewer [106] of the PDB [107] entries 2HYD and 2ONJ, as reported [104,108].

Figure 6

Classes of well-studied bacterial solute transporters. The bacterial outer and inner (cytoplasmic) membranes are shown. Also depicted are the cytoplasmic and periplasmic spaces. P_i denotes phosphate, and Na⁺ and H⁺ denote sodium and proton, respectively. This figure kindly provided courtesy of Ann F. Varela.

Figure 7

Crystal structure of E. coli MdfA multidrug efflux pump from the MFS. The MdfA transporter is complexed to one of its substrates, chloramphenicol (ball and stick structure). Ribbons of different colors represent the transmembrane helices. The loops between the transmembrane domains were removed for clarity. The model of the MdfA structure was generated using NGL Viewer [106] from the Protein Database, PDB [107], entry 4ZOW from Heng et al. [130].

Figure 8

Outer membrane protein, OmpF, is a porin from Escherichia coli. The OmpF porin is a trimeric apparatus consisting of three monomers. The OmpF porin structure was generated with the NGL Viewer [106] from the Protein Database, PDB [107], entry 2OMF from Cowan et al. [174].