Molecular Mechanisms of Antibiotic Resistance: The Need for Novel Antimicrobial Therapies

Abstract

Despite the enormous success of antibiotics as chemotherapeutic agents, infectious diseases remain a leading cause of mortality worldwide. Bacteria coevolving with infectious microorganisms have been driven to develop protection against environmental bioactive chemicals, and to resist their own antibiotics and defense compounds. Such resistance in pathogenic microorganisms provides protection against chemotherapeutic intervention and can lead to infections that are notoriously difficult to manage. Here, we introduce briefly the molecular mechanisms of action for common antibiotic classes and the structural determinants of bacterial resistance to antibiotics. Bacterial resistance to antibiotics interfering with cell wall biosynthesis is discussed with examples from b-lactams and glycopeptides. The molecular determinants of bacterial tolerance to protein biosynthesis inhibitors are analyzed with examples from aminoglycosides, marcolides and tetracyclines. Fluoroquinolone tolerance is described in connection with DNA regulation in the presence of inhibitors. The action of b-lactam and glycopeptides antibiotics, which target cell wall biosynthesis, is evaded through target modifications and antibiotic deactivation. bLactamases can be deployed to deactivate b-lactam antibiotics, while penicillinbinding proteins with altered binding sites provide an example of modification of the antibiotic target. Alteration of peptidoglycan peptide termini helps protect cell wall synthesis from glycopeptides, while reduced cross-linking and thickened cell wall obstruct glycopeptides access at the cell wall periphery. Specific molecular changes within ribosomal structures can foil aminoglycoside, tetracycline or macrolide attack. Further protection can be achieved by positioning proteins to protect protein synthesizing machinery from the action of tetracyclines. Important resistance mechanisms protecting bacterial protein synthesis include enzymatic deactivation of aminoglycosides and efflux systems expelling incoming macrolides, aminoglycosides and tetracyclines. Renewed efforts to explore alternative strategies for infection management have brought to the top of scientific agenda defense peptides, lanthionine antibiotics, phage therapies and other antimicrobial techniNew Strategies Combating Bacterial Infection. Edited by Iqbal Ahmad and Farrukh Aqil

Targeting Salmonella Typhimurium Invasion and Intracellular Survival Using Pyrogallol

“…Besides, these bacteria developed strategies to evade the host defense mechanism, invade the cells and reside intracellularly. Moreover, regardless of the possibility of developing new antimicrobials, microbial agents acquire resistance to various drugs (Hrvatin, 2017). Even though quinolones are referred to as the therapeutic options against intracellular pathogens, multiple bacteria are developing resistance against these conserved groups of antimicrobial agents (Van Bambeke et al, 2005).…”

Use of Plant Extracts, Bee-Derived Products, and Probiotic-Related Applications to Fight Multidrug-Resistant Pathogens in the Post-Antibiotic Era

“…Understanding the molecular mechanisms underlying antimicrobial (antibiotic or antifungal) resistance is essential, and it requires a deep knowledge of microbial structures and their metabolic functions. Structural and metabolic differences between microorganisms and host cells make it possible to selectively kill the pathogen, or at least inhibit its growth with antimicrobial agents [21], thus allowing the host immune system to eliminate the infection [7]. AMR in pathogens (particularly in bacteria) has emerged as a global challenge since antibiotics were first administered, as it threatens the effectiveness of clinical treatments.…”

‘There is worse to come’: The biopolitics of traumatism in antimicrobial resistance (AMR)

“…A 2008 paper fuses militaristic and epochal metaphors: ‘the age of antibiotic therapy has come to an end. … we have struggled in a ceaseless war with resistance where bacteria have adapted quickly … threatening a return to the “dark ages” of the pre-antibiotic era…’ (Dale-Skinner and Bonev, 2008: 40).…”