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.2016 Dec 8:7:13803.
doi: 10.1038/ncomms13803.

A diverse intrinsic antibiotic resistome from a cave bacterium

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A diverse intrinsic antibiotic resistome from a cave bacterium

Andrew C Pawlowski et al. Nat Commun..

Abstract

Antibiotic resistance is ancient and widespread in environmental bacteria. These are therefore reservoirs of resistance elements and reflective of the natural history of antibiotics and resistance. In a previous study, we discovered that multi-drug resistance is common in bacteria isolated from Lechuguilla Cave, an underground ecosystem that has been isolated from the surface for over 4 Myr. Here we use whole-genome sequencing, functional genomics and biochemical assays to reveal the intrinsic resistome of Paenibacillus sp. LC231, a cave bacterial isolate that is resistant to most clinically used antibiotics. We systematically link resistance phenotype to genotype and in doing so, identify 18 chromosomal resistance elements, including five determinants without characterized homologues and three mechanisms not previously shown to be involved in antibiotic resistance. A resistome comparison across related surface Paenibacillus affirms the conservation of resistance over millions of years and establishes the longevity of these genes in this genus.

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Figures

Figure 1
Figure 1. The antibiotic resistance genotype ofPaenibacillus sp. LC231.
The Comprehensive Antibiotic Resistance Database (CARD) annotated nine resistance genes and one resistant variant from the draft genome sequence. For phenotypes where a genotype could not be identified, functional genomics was employed, identifying eight resistance elements, including five novel gene families.
Figure 2
Figure 2.Paenibacillus sp. LC231 inactivates bacitracin through amidohydrolysis.
(a) Structure of bacitracin highlighting asparagine-12. (b) Structure of bacitracin A bound to geranyl-pyrophosphate (PDB 4K7T). Hydrogen bonding between bacitracin and the pyrophosphate moiety is indicated with dashed lines. (c) Molecular fragments of bacitracin and inactive bacitracin (R12->D12) identified using tandem mass spectrometry. The observed fragments correspond to the ring portion of the structure. Residues in each fragment correspond to the numbering ina. (d) Bacitracin inactivation byE. coli BL21(DE3) pET11a-bahA assayed using a Kirby–Bauer assay.
Figure 3
Figure 3. CpaA is a novel capreomycin acetyltransferase.
(a) CpaA specifically modifies capreomycin. A spectrophotometric assay was used to monitor acetylation of capreomycin, viomycin or kanamycin by CpaA. (b) Structure of capreomycin highlighting the site of CpaA acetylation. Arrows and bold bonds represent important correlations in multi-dimensional NMR experiments. Arrows represent important multi-bond heteronuclear multiple-bond correlation spectroscopy (HMBC) correlations and bold bonds represent multi-bond total correlation spectroscopy (TOCSY) and heteronuclear single-quantum correlation spectroscopy (HSQC) correlations.
Figure 4
Figure 4. MphI is a macrolide kinase with novel substrate specificity.
(a) A selection of macrolides were examined for phosphorylation by MphI. (b) The chemical structure of clarithromycin highlighting the site of Mph phosphorylation and the C3 position. Below, the expected and observed masses for clarithromycin, descladinose clarithromycin and the phosphorylated products. (c) MphI phosphorylation of descladinose clarithromycin. (d) As a control, a similar reaction was performed using clarithromycin.
Figure 5
Figure 5. The conservation of resistance over millions of years.
(a) Ten resistance enzymes were compared across a single clade of thePaenibacillus species tree containing the closest surface relatives toPaenibacillus sp. LC231. The species tree is presented as a dendrogram. The presence or absence of each enzyme is indicated and the pair-wise sequence identity shown as a heat map. Background colour indicates that the enzyme was not detected. (b,c) The genomic location ofvat (b) andcpa (c) genes across a subset of genomes reveals differing genomic context and synteny despite sequence conservation. An assembly gap in Rph fromPaenibacillus sp. HGF5 is indicated with an asterisk.
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References

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