Revisiting Antibiotic Resistance: Mechanistic Foundations to Evolutionary Outlook

Abstract

Antibiotics are the pivotal pillar of contemporary healthcare and have contributed towards its advancement over the decades. Antibiotic resistance emerged as a critical warning to public wellbeing because of unsuccessful management efforts. Resistance is a natural adaptive tool that offers selection pressure to bacteria, and hence cannot be stopped entirely but rather be slowed down. Antibiotic resistance mutations mostly diminish bacterial reproductive fitness in an environment without antibiotics; however, a fraction of resistant populations 'accidentally' emerge as the fittest and thrive in a specific environmental condition, thus favouring the origin of a successful resistant clone. Therefore, despite the time-to-time amendment of treatment regimens, antibiotic resistance has evolved relentlessly. According to the World Health Organization (WHO), we are rapidly approaching a 'post-antibiotic' era. The knowledge gap about antibiotic resistance and room for progress is evident and unified combating strategies to mitigate the inadvertent trends of resistance seem to be lacking. Hence, a comprehensive understanding of the genetic and evolutionary foundations of antibiotic resistance will be efficacious to implement policies to force-stop the emergence of resistant bacteria and treat already emerged ones. Prediction of possible evolutionary lineages of resistant bacteria could offer an unswerving impact in precision medicine. In this review, we will discuss the key molecular mechanisms of resistance development in clinical settings and their spontaneous evolution.

Keywords: adaptation; antibiotic resistance; bactericide; bacteriostatic; clonal interference; compensatory evolution; drug interaction; epistasis; evolution; mutant selection window.

Figure 1

Historical panorama of antibiotic launch and resistance detection. The x-axis indicates different types of antibiotics and the corresponding y-axis shows the year of introduction into clinical practices. Resistance histories to different antibiotics are shown by different circles. Connecting line between empty and filled coloured circles shows the year of introduction of a specific antibiotic into clinical practice and the year of resistance observed for that antibiotic; each coloured circle further represents different bacterial species. For example, colistin was first introduced into clinical practice in 1952 [13], but resistance to colistin was first reported in clinical P. aeruginosa and K. pneumoniae (shown by a specific coloured circle) in 1998 [14]. Penicillin resistant laboratory E. coli was reported in 1950 [15] before its introduction into clinical practice in 1941, but the first penicillin resistance clinical S. aureus was reported in 1942 [16,17]. PDR: pan-drug resistant; VR: vancomycin resistant; spp: species; ND: resistance mechanism not detected.

Figure 2

Diversity of antibiotic resistance mechanisms. The figure shows the major bactericidal antibiotics and their different targets. Beta-lactam antibiotics degrade bacterial cell wall by interfering with cross-linking or transpeptidations within the bacterial cell wall by binding with PBP (panel A), aminoglycoside interferes with protein synthesis by binding with 30S ribosomal subunit (panel B), rifamycin inhibits bacterial transcription by interfering with beta-subunit of DNA dependent RNA polymerase enzyme (panel C), whereas quinolone class of antibiotics inhibit DNA synthesis by interfering with DNA topoisomerase (panel D). OM: outer membrane; PGL: peptidoglycan layer; IM: inner membrane; PBP: penicillin binding protein. Mechanism of action of polymyxin and daptomycin is provided in the text.

Figure 3

Active efflux pumping system to eliminate antibiotics from the periplasm. Efflux pump is associated with intrinsic antibiotic resistance. Intrinsic resistance is considered as phenotypic resistance as tolerance is not mediated by any genetic mutation. A = beta-lactam antibiotic which binds to the penicillin binding protein (PBP) and destabilizes peptidoglycan; B = aminoglycoside antibiotic; C = polymyxin antibiotic. Most notably, decreased susceptibility mediated by efflux system is mostly linked with aminoglycosides and fluoroquinolone, which is predominantly observed in Gram-negative bacteria.

Figure 4

Trinity of horizontal resistance gene transfer modalities. Transmission of genetic material by horizontal genetic transfer, which is accomplished by three different mechanisms: transformation—bacteria take up naked DNA from the environment and integrate it to their chromosomes (1), transduction—bacteriophages carry resistance genes and transfer them to multiple hosts (2), and conjugation—resistance genes are transferred between bacterial cells through cell-to-cell contact (3).

Figure 5

Antibiotic resistance via acquisition of mobile genetic elements (MGEs). The structure of a resistance plasmid (R100) (panel A) and the process of resistance gene acquisition (panel B) are illustrated. Resistant plasmid harbouring many different resistance genes as part of transposon (Tn) element can confer multidrug resistance by a single conjugation event. Integron mediated resistance gene capture system is frequently observed in many different clinical bacterial species. Integrase (transcribed under a downstream promoter (Pint)) catalyzes the insertion of an integron. Resistance gene cassette 1 (blue) is integrated into the attI site, which is under the influence of an upstream promoter (Pant). This way, many different resistance genes can be captured repeatedly for example, resistance gene 2. All resistance genes remain under the same promoter and thus become a resistance operon. Tn: transposon; bp: base-pair; tet: tetracycline resistance gene; cat: chloramphenicol acetyltransferase; sul1: sulphonamide resistance gene; aadA1: aminoglycoside adenylyltransferase; mer: mercury resistance gene; qacE: quaternary ammonium compound-resistance gene.