INTRODUCTION :
Darobactin represents a new class of antibiotics specifically designed to target gram negative bacteria . It is derived from symbiotic bacteria found in entomopathogenic nematodes , it demonstrates potent activity against a wide range of gram negative pathogens , including drug resistant strains . This groundbreaking discovery offers a promising solution for treating infections caused by multi drug resistant Gram negative pathology.
It is and experimental antibiotic and its unique mechanism involve binding to Bam A , an essential protein in bacterial outer membrane , disrupting its function and leading to bacterial death.
HISTORY AND BACKGROUND :
Darobactin was discovered in 2019 by a team of researchers led by Kim Lewis and colleagues at Northeastern University . It was identified through a novel screening approach using Photorhabdus khanii , a symbiotic bacterium found in the gut of entomopathogenic nematodes - organisms that naturally infect and kill insects . This bacterium produces darobactin as a part of its arsenal help to help the nematode suppress host defenses and establish infection.
They also screened Xenorhabdus strains. IDENTIFICATION : . Darobactin is a modified heptapeptide with an amino acid sequence W1 -N 2 -W3 -S 4 -K 5 -S 6 -F 7 . NMR studies revealed two unusual macrocycle cross linkages in darobactin: an unprecedented aromatic-aliphatic ether linkage between the C7 indole of W1 and the β-carbon of W3 , and a carbon-carbon bond between the C6 indole of W3 and the β-carbon of K5 . The tryptophan-lysine bond is made between two unactivated carbons, which is unique for an antibiotic.
UNIQUE FEATURES OF DAROBACTIN :
1) Natural Product : Darobactin is a ribosomally synthesized and post transitionally modified peptide (RiPP) . Derived from bacterial ribosome , it undergoes modification to gain its active form.
2) Structure : Unusual structure with macrocyclic rings formed through post - transitional modifications contributing to its stability and activity against Gram Negative pathogens.
UNIQUE MECHANISM OF ACTION :
It is particularly significant because it selectively targets gram negative bacteria which are notoriously difficult to treat due to their robust double outer membrane structure that limits antibiotic penetration. It works by binding to Bam A ( ß- barrel assembly machine A) and essential protein involved in the bio-genesis of bacterial outer membrane disrupting its function and ultimately leading to bacterial death .
Identifying the target Darobactin had reasonable activity against a range of Gram-negative bacteria, with an MIC of 2 µg ml-1 against important drug-resistant pathogens, E. coli and K. pneumoniae, including polymyxin resistant, ESBL (extended spectrum β-lactamase) and carbapenem resistant clinical isolates . The compound is bactericidal ( with an MBC of 8 µg ml-1 against E. coli. There was little activity against Gram-positive bacteria. Interestingly, the compound was also largely inactive against gut commensal, including Bacteroides, the main group of Gram-negative symbionts24. Disrupting the microbiome by antibiotics, especially early in life, is a major concern, given the important role of symbiotic bacteria in many aspects of human health, such as shaping the immune system during development.
CLINICAL POTENTIAL :
A major breakthrough is darobactin’s effectiveness against gram negative pathogens including a new mechanism of action against multi drug resistant strains like Escherichia coli , Klebsiella pneumoniae and Acinetobacter baumannii. Its activity has been demonstrated in pre-clinical models where it showed significant efficacy in treating infections.
SIGNIFICANCE OF DISCOVERY:
The discovery of darobactin highlights the importance of exploring unconventional sources of antibiotics , such as natural symbiotic relationships in microbes. As antibiotic resistance continues to rise , darobactin provides a promising avenue for addressing the urgent need for novel treatments.
FUTURE PROSPECTS :
Since its discovery, researchers have been working to:
Optimize darobactin's pharmacokinetics and pharmacodynamics for clinical use.
Understand and overcome potential resistance mechanisms.
Explore synthetic modifications to improve efficacy and broaden its spectrum of activity.
While still in early stages of development , darobactin represents a hopeful step forward . Research is ongoing to further refine its structure , optimize its efficacy and evaluate its safety profile for eventual clinical use . Its novel mechanism and natural origin mark it as a cornerstone in the fight against antibiotic resistance. REFERENCES :
-By Sparsha Jani
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