Unique Antibiotic Mechanism Developed

A new class of antibiotic developed at the Synthetic Biology Centre at Massachusetts Institute of Technology may play a big part in the ongoing battle against antibiotic resistance.

The new antibiotic mechanism, designed by Professor Timothy Lu, involves the use of antimicrobials which specifically target genes associated with harmful bacteria.

Lu claims that the problem of antibiotic resistance is being driven by the use of current antibiotics, explaining that as currently used antibiotics tend to be broad spectrum, their use results in “indiscriminate killing” of both good and bad bacteria, leading to the “accelerated evolution of drug resistance.” (1)

By specifically targeting harmful bacteria, it is hoped that the new mechanism will be able to fulfil the role of classic antibiotics whilst not encouraging antibiotic resistance.

Antibiotic - Biological Mechanisms of Resistance

Resistance Mechanisms toward traditional antibiotics
There are various mechanisms by which bacteria can resist traditional antibiotics. The use of antibiotics creates a selective pressure that encourages the honing and specification of these mechanisms.

Antibiotic - Biological Mechanisms of Resistance

Resistance Mechanisms toward traditional antibiotics
There are various mechanisms by which bacteria can resist traditional antibiotics. The use of antibiotics creates a selective pressure that encourages the honing and specification of these mechanisms.

Antibiotic - Biological Mechanisms of Resistance

Resistance Mechanisms toward traditional antibiotics
There are various mechanisms by which bacteria can resist traditional antibiotics. The use of antibiotics creates a selective pressure that encourages the honing and specification of these mechanisms.

Antibiotic - Biological Mechanisms of Resistance

Resistance Mechanisms toward traditional antibiotics
There are various mechanisms by which bacteria can resist traditional antibiotics. The use of antibiotics creates a selective pressure that encourages the honing and specification of these mechanisms.

Growing antibiotic resistance has long been acknowledged as a serious issue in the scientific community, with the Chief Medical Officer for England Prof Dame Sally Davies last year summarising the community’s fears by referring to the problem as a “ticking time bomb” and “catastrophic threat.”(2)

The issue has even been directly addressed by world leaders; the United Kingdom Prime Minister David Cameron has expressed fears that society may be “cast back into the dark ages of medicine” if drastic action is not taken, whilst in the US the Obama administration recently announced it will be taking measures to restrict the overuse of antibiotics.(3)

The new mechanism was developed by taking advantage of the bacterial CRISPR system, which is a mechanism used by bacteria as a defence against bacteria-specific viruses, termed bacteriophages.

The system involves RNA-guided nucleases (RGNs) which have the ability to target and destroy specific bacterial genes. By targeting the nucleases to genes associated with antibiotic resistance or virulence, the mechanism can be used to selectively destroy harmful bacteria whilst having no effect on harmless, commensal bacteria.

Using modified bacteriophages, RGN constructs are delivered indiscriminately into both good and bad bacteria living in the host. Once inside bacteria the construct is expressed, leading to RGN production. In harmful bacteria the cell is destroyed as the newly produced RGN targets and digests specific genes, whilst in harmless commensal bacteria, which lack the targeted genes, RGN exerts no effect. (1)

Antibiotic - RGN constructs delivered by bacteriophage particles (ΦRGN) exhibit efficient and specific antimicrobial effects against strains harboring plasmid or chromosomal target sequences.

RGN constructs delivered by bacteriophage particles (ΦRGN) exhibit efficient and specific antimicrobial effects against strains harboring plasmid or chromosomal target sequences.

Once delivered into a cell, the RGN construct will attempt to locate / destroy the target gene:
  1. If the gene is absent (i) then the construct will exert no effect.
  2. If the gene is chromosomal (ii) its destruction by RGN will result in cell death.
  3. If the gene is episomal (iii), so existing on a plasmid, the cell will either die or just experience loss of the plasmid, depending on whether or not a biochemical mechanism termed the “toxin-antitoxin system” is present.

Antibiotic - RGN constructs delivered by bacteriophage particles (ΦRGN) exhibit efficient and specific antimicrobial effects against strains harboring plasmid or chromosomal target sequences.

RGN constructs delivered by bacteriophage particles (ΦRGN) exhibit efficient and specific antimicrobial effects against strains harboring plasmid or chromosomal target sequences.

Once delivered into a cell, the RGN construct will attempt to locate / destroy the target gene:
  1. If the gene is absent (i) then the construct will exert no effect.
  2. If the gene is chromosomal (ii) its destruction by RGN will result in cell death.
  3. If the gene is episomal (iii), so existing on a plasmid, the cell will either die or just experience loss of the plasmid, depending on whether or not a biochemical mechanism termed the “toxin-antitoxin system” is present.

Antibiotic - RGN constructs delivered by bacteriophage particles (ΦRGN) exhibit efficient and specific antimicrobial effects against strains harboring plasmid or chromosomal target sequences.

RGN constructs delivered by bacteriophage particles (ΦRGN) exhibit efficient and specific antimicrobial effects against strains harboring plasmid or chromosomal target sequences.

Once delivered into a cell, the RGN construct will attempt to locate / destroy the target gene:
  1. If the gene is absent (i) then the construct will exert no effect.
  2. If the gene is chromosomal (ii) its destruction by RGN will result in cell death.
  3. If the gene is episomal (iii), so existing on a plasmid, the cell will either die or just experience loss of the plasmid, depending on whether or not a biochemical mechanism termed the “toxin-antitoxin system” is present.

Antibiotic - RGN constructs delivered by bacteriophage particles (ΦRGN) exhibit efficient and specific antimicrobial effects against strains harboring plasmid or chromosomal target sequences.

RGN constructs delivered by bacteriophage particles (ΦRGN) exhibit efficient and specific antimicrobial effects against strains harboring plasmid or chromosomal target sequences.

Once delivered into a cell, the RGN construct will attempt to locate / destroy the target gene:
  1. If the gene is absent (i) then the construct will exert no effect.
  2. If the gene is chromosomal (ii) its destruction by RGN will result in cell death.
  3. If the gene is episomal (iii), so existing on a plasmid, the cell will either die or just experience loss of the plasmid, depending on whether or not a biochemical mechanism termed the “toxin-antitoxin system” is present.

It is well established that commensal bacteria play a large, positive role in human health (4), and fears that the overuse of currently favoured, broad spectrum antibiotics could damage human health by destroying these commensal bacteria have been expressed by various academics.(5)(6)

In March 2011 the respected journal Nature published a commentary by Martin Blaser, Professor of Translational Medicine at York University School of Medicine, in which Blaser explained how the overuse of current antibiotics may be leading to devastating long-term consequences.

“Antibiotics kill the bacteria we do want, as well as those we don’t. Early evidence from my lab and others hints that, sometimes, our friendly flora never fully recover. These long-term changes … may even increase our susceptibility to infections and disease. Overuse of antibiotics could be fuelling the dramatic increase in conditions such as obesity, type 1 diabetes, inflammatory bowel disease, allergies and asthma.” (7)

Blaser concluded his commentary by acknowledging the need for “new, narrow-spectrum antibacterial agents to minimize collateral effects on the microbiota”, which is exactly what Professor Lu and his team have now designed.

Lu hopes that his work will aid other research teams battling the problem of antibiotic resistance, stating that his method of design has “the potential to reinvigorate the pipeline for new antimicrobials.”(1)

Antibiotic - Concerns about antibiotics focus on bacterial resistance — but permanent changes to our protective flora could have more serious consequences.

Antibiotic Use and Inflammatory Bowel Diseases in Childhood

There is a strong and significant correlation between risk of inflammatory bowel disease and number of antibiotic courses taken in young children.

Antibiotic - Concerns about antibiotics focus on bacterial resistance — but permanent changes to our protective flora could have more serious consequences.

Antibiotic Use and Inflammatory Bowel Diseases in Childhood

There is a strong and significant correlation between risk of inflammatory bowel disease and number of antibiotic courses taken in young children.

Antibiotic - Concerns about antibiotics focus on bacterial resistance — but permanent changes to our protective flora could have more serious consequences.

Antibiotic Use and Inflammatory Bowel Diseases in Childhood

There is a strong and significant correlation between risk of inflammatory bowel disease and number of antibiotic courses taken in young children.

Antibiotic - Concerns about antibiotics focus on bacterial resistance — but permanent changes to our protective flora could have more serious consequences.

Antibiotic Use and Inflammatory Bowel Diseases in Childhood

There is a strong and significant correlation between risk of inflammatory bowel disease and number of antibiotic courses taken in young children.

References

  1. Robert J Citorik, Mark Mimee & Timothy K Lu; Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases [2014-09-21; Nature Biotechnology]
  2. Antimicrobial resistance poses ‘catastrophic threat’, says Chief Medical Officer [2013-03-12; Gov.uk]
  3. Antibiotic resistance: Cameron warns of medical ‘dark ages’ [2014-07-01; BBC News Health]
  4. Guarner F, Malagelada JR.; Gut flora in health and disease. [2003-02-08; National Center of Biotechnology Information]
  5. David L. Peterson; “Collateral Damage” from Cephalosporin or Quinolone Antibiotic Therapy [2004; Clinical Infectious Diseases]
  6. Hoban DJ.; Antibiotics and collateral damage [2003; National Center for Biotechnology Information]
  7. Martin Blaser; Antibiotic overuse: Stop the killing of beneficial bacteria [2011-08-24; Nature]

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Christopher Edward Jones is a biochemist and writer currently affiliated with Queen Mary University of London, where he is part of a research group focusing on the restriction factors of HIV. In the past he has worked with multiple biomedical research groups in both industry and academia. He has a research interest in the biochemical mechanisms of virus restriction and a general interest in all areas of science.

Christopher Edward Jones is a biochemist and writer currently affiliated with Queen Mary University of London, where he is part of a research group focusing on the restriction factors of HIV. In the past he has worked with multiple biomedical research groups in both industry and academia. He has a research interest in the biochemical mechanisms of virus restriction and a general interest in all areas of science.

Christopher Edward Jones is a biochemist and writer currently affiliated with Queen Mary University of London, where he is part of a research group focusing on the restriction factors of HIV. In the past he has worked with multiple biomedical research groups in both industry and academia. He has a research interest in the biochemical mechanisms of virus restriction and a general interest in all areas of science.

Christopher Edward Jones is a biochemist and writer currently affiliated with Queen Mary University of London, where he is part of a research group focusing on the restriction factors of HIV. In the past he has worked with multiple biomedical research groups in both industry and academia. He has a research interest in the biochemical mechanisms of virus restriction and a general interest in all areas of science.

The Michelson Medical Research Foundation‘s Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.
The Michelson Medical Research Foundation‘s Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.
The Michelson Medical Research Foundation‘s Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.
The Michelson Medical Research Foundation‘s Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.