Acquired inducible antimicrobial resistance in Gram-positive bacteria

Abstract

A major contributor to the emergence of antibiotic resistance in Gram-positive bacterial pathogens is the expansion of acquired, inducible genetic elements. Although acquired, inducible antibiotic resistance is not new, the interest in its molecular basis has been accelerated by the widening distribution and often 'silent' spread of the elements responsible, the diagnostic challenges of such resistance and the mounting limitations of available agents to treat Gram-positive infections. Acquired, inducible antibiotic resistance elements belong to the accessory genome of a species and are horizontally acquired by transformation/recombination or through the transfer of mobile DNA elements. The two key, but mechanistically very different, induction mechanisms are: ribosome-sensed induction, characteristic of the macrolide-lincosamide-streptogramin B antibiotics and tetracycline resistance, leading to ribosomal modifications or efflux pump activation; and resistance by cell surface-associated sensing of β-lactams (e.g., oxacillin), glycopeptides (e.g., vancomycin) and the polypeptide bacitracin, leading to drug inactivation or resistance due to cell wall alterations.

Figure 1. Representative mobile genetic elements carrying inducible resistance genes

(A) Conjugative transposon Tn916 and Tn916-like mosaic elements elements carrying inducible macrolide resistance (blue) and tetracycline resistance (yellow) genes. (B) Conjugative transposon Tn1546 encoding inducible vancomycin resistance. (C) Transposon Tn552 encoding inducible β-lactam resistance. (D) Staphylococcal cassette chromosome encoding resistance to β-lactams. Resistance determinants are indicated in blue; genes encoding regulatory (red) or accessory functions (black) for antibiotic resistance are also indicated. See text for details.

Figure 2. Translational and transcriptional attenuation of erm gene expression

(A) Translational attenuation of erm(C). In the absence of inducer, ribosomes translate the leader peptide (Erm(C)L) and dissociates allowing reformation of stem-loop 1 + 2. Stem-loop 3 + 4 (red) forms in the absence of inducer and blocks ribosome binding to the erm(C) RBS₂ thus preventing translation. In the presence of inducer, the ribosome stalls on erm(C)L disrupting stem-loop 1 + 2 and through formation of 2 + 3, prevents formation of 3 + 4 and promotes translation of the Erm(C). (B) Transcriptional attenuation of erm(K). In the absence of inducer, four stem-loop structures, including two Rho-independent transcriptional terminators (red) that prematurely terminate the erm(K) transcript. In the presence of inducer, refolding of the transcript disrupts both terminators allowing completion of the erm(K) transcript and subsequent translation of Erm(K). RBS: Ribosomal binding site.

Figure 3. Induction of antibiotic resistance via signal transduction systems

(A) Vancomycin, (B) β-lactams and (C) bacitracin. See text for details. P: Phosphate; TCS: Two-component system.

Figure 4. Organization of transferable van gene clusters

Produced precursors are (A) d-Ala-d-Lac and (B) d-Ala-d-Ser. The Streptomyces coelicolor van gene cluster (C) is shown for comparison.

Figure 5. Organization of the bla operon and SCCmec cassettes

^†Constitutive mecA expression; however, in the presence of the bla regulatory elements BlaI and BlaR1 mecA expression may be under regulatory control of these elements. ermA ars: Arsenic resistance. The classification is based on the information provided by the SCCmec website curated by the International Working Group on the Classification of Staphylococcal Cassette Chromosome Elements [202]. See text for further details.

Figure 6. Schematic organization of the bcrABD region on Enterococcus faecalis AR01/DGVS plasmid pJM01 (GenBank AY496968) and on the bcrABD and additional resistance determinant-containing part of E. faecalis plasmid TW9 (GenBank NC_014726)

Bacitracin resistance-associated genes are indicated in black, genes for other resistance determinants and their associated regulatory genes are indicated in dark gray, all other genes are indicated in light gray.