Antibiotics and Bacterial Resistance-A Short Story of an Endless Arms Race

Abstract

Despite the undisputed development of medicine, antibiotics still serve as first-choice drugs for patients with infectious disorders. The widespread use of antibiotics results from a wide spectrum of their actions encompassing mechanisms responsible for: the inhibition of bacterial cell wall biosynthesis, the disruption of cell membrane integrity, the suppression of nucleic acids and/or proteins synthesis, as well as disturbances of metabolic processes. However, the widespread availability of antibiotics, accompanied by their overprescription, acts as a double-edged sword, since the overuse and/or misuse of antibiotics leads to a growing number of multidrug-resistant microbes. This, in turn, has recently emerged as a global public health challenge facing both clinicians and their patients. In addition to intrinsic resistance, bacteria can acquire resistance to particular antimicrobial agents through the transfer of genetic material conferring resistance. Amongst the most common bacterial resistance strategies are: drug target site changes, increased cell wall permeability to antibiotics, antibiotic inactivation, and efflux pumps. A better understanding of the interplay between the mechanisms of antibiotic actions and bacterial defense strategies against particular antimicrobial agents is crucial for developing new drugs or drug combinations. Herein, we provide a brief overview of the current nanomedicine-based strategies that aim to improve the efficacy of antibiotics.

Keywords: antibiotic resistance; antibiotics; bacteria; mechanism of action.

Figure 1

Bactericidal mechanism of (1) β-lactams and (2) glycopeptide antibiotics; NAG—N-acetylglucosamine, NAM—N-acetylmuramic acid. Figure created with Biorender.com.

Figure 2

Mechanism of action of (1) the lipopeptide antibiotic daptomycin and (2) polymyxin. Figure created with Biorender.com.

Figure 3

Mechanism of action of quinolones in (1) Gram-positive and (2) Gram-negative bacteria. Figure created with Biorender.com.

Figure 4

A model of rifamycin action. Figure created with Biorender.com.

Figure 5

Mechanism of action of (1) tetracyclines; (2) aminoglycosides; (3) MLSB macrolides, lincosamides, and type B streptogramins; (4) oxazolidinones. Figure created with Biorender.com.

Figure 6

Mechanism of action of antibiotics targeting folic acid synthesis: (1) sulfonamides and (2) trimethoprim. Dihydropteroate synthase (DHPS), a critical enzyme in the formation of dihydrofolate, is inhibited by sulfamethoxazole, and dihydrofolate reductase (DHFR) is inhibited by trimethoprim. Figure created with Biorender.com.

Figure 7

Diagrammatic illustration of some possible resistance mechanisms based on target site modification of antibiotics: (1) alteration in PBP; (2) altered cell wall precursors; (3) modified or loss of lipopolysaccharide; (4) mutated DNA gyrase/topoisomerase IV or RNA polymerase; (5) alteration in the 30S or 50S subunit; (6) modified DHPS. Figure created with Biorender.com.

Figure 8

Reduced antibiotic accumulation through changes in the permeability of the bacterial cell. Figure created with Biorender.com.

Figure 9

Summary of the six major families of efflux transporters: MFS (a superfamily of the main facilitator), SMR (the small multidrug resistance family), PACE (proteobacterial antimicrobial compound efflux), MATE (multidrug and toxic compound extrusion family), ABC (ATP binding cassette superfamily) and RND (resistance nodulation division family). Figure created with Biorender.com.

Figure 10

Representation of the enzymatic inactivation of antibiotics through (1) hydrolysis, (2) group transfer, and (3) the redox process. Figure created with Biorender.com.

Figure 11

New therapeutic approaches using antibiotics to combat multidrug-resistant bacteria: (1) phage-antibiotic synergy (PAS), (2) nucleotide metabolism contributes to antibiotic lethality, (3) conjugate therapy (nanotechnology + antibiotics), (4) microbiota as a source of new antibiotics. Figure created with Biorender.com.