About AMR: Antibiotic resistance genes – old dog with new tricks

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In a recent study published in Nature Communications, Jiang and colleagues investigated the ‘producer hypothesis’ of antibiotic resistance gene (AGR) origin. They provide bioinformatics evidence of AGR transfer from producing species to modern-day pathogens and use experimental evidence to support a new model of transfer. Their finding of a recent transfer event highlights the importance of considering the environmental resistome as a reservoir of antibiotic resistance when developing new therapeutics.

Many current antibiotics are natural products isolated from soil-dwelling microorganisms that use the active compounds to kill or inhibit competitors in their ecological niche. To prevent self-inflicted damage, the producing organisms encode mechanisms of resistance that modify or inactivate the antibiotic. The antibiotic resistance mechanisms found in Gram-negative pathogens are often reminiscent of those found in the environment, leading scientists to hypothesize that modern-day antibiotic resistance originated from the producing organisms.

Issues with this ‘producer hypothesis’ include the challenge of DNA transfer across evolutionary distinct phyla of bacteria. The most common antibiotic producers are Streptomyces species – Gram-positive bacteria of the actinobacteria phylum. However, horizontal gene transfer from actinobacteria to the proteobacteria phylum, which includes antibiotic-resistant Gram-negative bacteria, has not been described. There is also limited sequence homology between some antibiotic resistance genes in pathogenic bacteria and producing strains, and few overlapping environments where transfer could occur.

To resolve this, the researchers consulted ARG databases to generate a list of all validated sequences of ARGs from Streptomyces species, and then used the list to search for similar sequences in proteobacteria. This approach revealed 12 potential transfer events of genes from Streptomyces to proteobacteria.

One of the 12 genes, the chloramphenicol exporter cmx, contained features consistent with a recent transfer event. Cmx is present in clinical isolates of Pseudomonoas aeruginosa, Klebsiella oxytoca and Enterobacter absuriae and shares significant homology with the chloramphenicol resistance protein in Streptomyces species. In both actinobacteria and proteobacteria, cmx is colocalized with a transposase gene, yet when tested experimentally, transposition of cmx alone was not sufficient to confer interphylum transfer.

Rather, the researchers proposed a multistep model of transfer, initiating with transfer of a conjugative plasmid from proteobacteria to actinobacteria, a process much more efficient than the reverse. The cmx gene is then transferred from the actinobacteria genome to the plasmid through transposition. Following cell death, the resistance plasmid is released into the environment where it can be taken up by naturally competent proteobacteria. Since the plasmid retains proteobacteria signatures, it is incorporated into the recipient organism through homologous recombination. The authors refer to this process as the ‘carry-back’ model and, in the case of cmx, identify the DNA sequence that acts as a molecular boomerang between organisms.

Recreating this in the lab, they found that exposing a recipient proteobacterium to lysed actinobacteria that contained the cmx gene on the ‘carrier’ plasmid results in transfer of the cmx gene to the recipient.

The model provides a solution to the barrier of DNA transfer across phylogenetic boundaries and supports the hypothesis that ARGs are at least in some cases, of an environmental origin, explaining the seemingly inevitability of antibiotic resistance. With the increasing threat of superbugs, the need to develop new antibiotics is one of the biggest challenges facing modern medicine. Without knowledge of ARG origin, the effectiveness of a new drug is essentially unpredictable. This study highlights that the environmental resistome is of clinical relevance and its use as a predictive tool might prove advantageous to minimizing the development of drugs with high likelihood of resistance.

Source:  Jiang X, Ellabaan MMH, Charusanti P et al. Dissemination of antibiotic resistance genes from antibiotic producers to pathogens. Nat. Comms. 8(15784) doi:10.1038/ncomms15784 (2017).

About the author

Julie Kaiser is a Ph.D. candidate in Microbiology at the University of Western Ontario in London, Canada. Her research interests range from the impact of microbial communities on human health, to the molecular basis of drug-resistant bacterial infections. Julie enjoys sharing her love for the microbial world through science communication and is the author of Microbiology for Dummies. Follow her on twitter at @jukais.

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