Darobactin is a recently identified antibiotic, offering a potential solution in the ongoing struggle against antibiotic resistance. This discovery is particularly notable given the increasing ineffectiveness of many existing treatments.
Discovery of Darobactin
The discovery of darobactin in 2019 involved an innovative approach to finding new antibiotics. Scientists utilized iChip technology, a method that allows researchers to grow microorganisms directly in their natural environment. This technique enabled the isolation of a bacterium from the gut of a nematode, a parasitic worm.
The bacterial source identified was Photorhabdus khanii HGB1456, which lives in symbiosis with these nematodes. This bacterium produces darobactin, which helps the nematodes by killing harmful bacteria in their insect hosts while sparing their beneficial gut bacteria.
How Darobactin Works
Darobactin exhibits a unique mechanism of action. It specifically targets the β-barrel assembly machinery (BAM) complex, located in the outer membrane of Gram-negative bacteria. This BAM complex is responsible for the proper folding and insertion of proteins into the bacterial outer membrane, a structure that acts as a protective barrier.
Darobactin binds to BamA, a subunit of the BAM complex, and disrupts its function. This interference prevents the bacteria from properly forming or repairing their outer membrane, leading to cell death. The interaction between darobactin and BamA makes it robust against potential resistance mutations. This novel target and mechanism of action are significant because many current antibiotics struggle to penetrate the double membrane of Gram-negative bacteria or are rendered ineffective by existing resistance mechanisms.
Why Darobactin Matters
The emergence of darobactin is particularly significant due to the global health challenge posed by multidrug-resistant Gram-negative bacteria. These bacteria, including Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, are difficult to treat because their outer membrane acts as a formidable barrier against many antibiotics. The World Health Organization (WHO) has categorized several of these pathogens as high-priority due to their increasing resistance to available drugs.
Darobactin offers a potential solution by targeting BamA, bypassing the need to penetrate the inner layers of the bacterial cell. This external targeting mechanism is an advantage, as it avoids common resistance pathways like efflux pumps or modifications to internal bacterial targets. The selective activity of darobactin against Gram-negative bacteria, while largely sparing beneficial gut bacteria, also represents a favorable characteristic, potentially reducing side effects associated with broad-spectrum antibiotics.
Current Research and Future Outlook
Current research on darobactin focuses on advancing its development as a therapeutic agent. Scientists have created modified versions of darobactin, such as darobactin D22, which demonstrate improved antibacterial activity. These engineered derivatives have shown promise in animal models, effectively inhibiting infections caused by Acinetobacter baumannii in zebrafish embryos and limiting Pseudomonas aeruginosa growth in mice.
In mice models, multiple doses of D22 have been shown to clear E. coli in severe abdominal infections and significantly reduce bacterial presence in urinary tract infections. While darobactin and its derivatives are still in preclinical stages, these early results are encouraging. The path to bringing a new antibiotic to market involves extensive testing for safety and efficacy, scaling up production, and navigating regulatory approvals, a process that can take many years. Continued research aims to optimize darobactin’s properties and assess its full potential for clinical use.