Chapter 9 : Bacterial Antibiotic Resistance: Overview

Coevolution of antibiotic regulation, biosynthesis, and self-protection. Self-protection equals resistance.

Schematic of antibiotic resistance mechanisms in bacteria. Genetic mechanisms 1 to 4 involve gene mutation and three routes for transfer of foreign genes (transformation, transduction, and conjugation). Molecular mechanisms A to D of resistance include exclusion by antibiotic efflux pumps, alteration of outer membrane porins, modification of antibiotic targets, and inactivating modifications of the antibiotic.

Major categories of antibiotic resistance. Susceptible Gram-negative bacteria take up antibiotic through wild-type (WT) porin, and the antibiotic inhibits the WT target. (a) Resistance via altered porin structure or abundance. (b) Resistance via active efflux. (c) Altered target in resistant mutants. (d) Destruction/modification of antibiotic, typically via deactivating enzymes, before it can inhibit its target.

Exclusion of β-lactams and fluoroquinolones by alteration of pore size in outer membrane OmpC porins from uropathogenic E. coli (Lou et al., 2011). (a) OmpC is embedded in the outer lipid membrane as a trimer. (b) A top view reveals the three pores of the OmpC trimer with the constriction helix shown in blue. (c) Residues shown in space-filling models represent the constriction zone of each OmpC pore, with residues shown in red representing known sites of mutation in antibiotic clinical isolates. (d) Structures and space-filling models of meropenem, a carbapenem β-lactam antibiotic, and ciprofloxacin, a fluoroquinolone antibiotic. Both antibiotics are excluded from E. coli cells with mutations in the OmpC constriction zone.

Resistance genes can be clustered within biosynthetic gene clusters. (a) The Bacillus cereus thiocillin-producing strain contains tclQ and tclT, which encode alternate forms of the L11 ribosomal subunit to generate ribosomes resistant to thiocillin. (b) The thienamycin producer carries a β-lactamase gene, thnS, encoded within the thienamycin biosynthetic cluster.

Macrolide self-protection in the oleandomycin producer involves intracellular glucosylation at the 3-OH of the macrolide scaffold by the glucosyltransferase OleI. The inactive glucosylated product is exported via the dedicated efflux pump OleB. In the external medium, the glucosyl protecting group is removed by action of OleR (see Walsh [2003], for more information).

(a) Antibiotic exclusion can occur as bacteria morph from free-living planktonic forms to communal biofilms. (Reprinted from Monroe [2007], licensed under CC-BY-3.0 [https://creativecommons.org/licenses/by/3.0/].) (b) In this schematic, cells deep in biofilms escape cell killing, in significant part by decreased access for antibiotics.

Two-component system logic for sensing an antibiotic and turning on a transcriptional response that leads to a resistance phenotype.

A conjugate of the aminoglycoside antibiotic to a membrane-penetrating peptide termed pentobra is effective against persisting strains of E. coli and S. aureus which typically display reduced metabolism and activity of transporters as one means of surviving antibiotic therapy.

Multiple-drug-resistant phenotypes are the default pattern for actinobacteria in environmental soils. (Reprinted from D'Costa et al. [2006] with permission.)

Venn diagram of contributors to the antibiotic resistome. Within a global pool of precursor genes are a subset that have evolved as cryptic genes ready to be mobilized and expressed, self-resistance genes in antibiotic producers, and resistance genes expressed in bacterial pathogens. (Adapted from Wright [2007].)

How does nature manage resistance? A steeply rising frequency of antibiotic resistance in clinics contrasts with a constant frequency of resistance in soil bacterial populations. (Reprinted from Chait et al. [2012] with permission.)

Mutations that lead to linezolid resistance are clustered in the nucleotides that comprise the 23S rRNA binding site for linezolid. (a) Three-dimensional view of linezolid and first-shell nucleotides in the peptidyltransferase center of the 50S subunit. (b) Two-dimensional representation of site of base changes that lead to resistance in both laboratory and clinical settings. Ec, E. coli; Es, Enterococcus faecalis; Em, Enterococcus faecium; Ms, Mycobacterium smegmatis; Mt, M. tuberculosis; Hh, Halobacterium halobium; Sa, S. aureus; Sh, Staphylococcus haemolyticus; Se, Staphylococcus epidermidis; Sp, Streptococcus pneumoniae. (Images from Long and Vester [2012], used with permission.)

Resistance timeline by organism during the 60 years from 1950 to 2010. (Reprinted from Madigan et al. [2012] with permission.)