Darobactin A

Darobactin A is a bactericidal antibiotic that selectively targets Gram-negative pathogens, including drug-resistant strains[1][2]. It is produced by the bacterium Photorhabdus khanii and has been found to have reasonable activity against a range of Gram-negative bacteria, including Escherichia coli and Klebsiella pneumoniae, with a minimum inhibitory concentration (MIC) of 2 μg ml−1[1]. Darobactin A is bactericidal, with a minimum bactericidal concentration (MBC) of 8 μg ml−1 against E. coli[1].

The compound has been shown to have little activity against Gram-positive bacteria and is largely inactive against gut commensals, including Bacteroides, which is the main group of Gram-negative symbionts[1]. This is significant because disrupting the microbiome, especially early in life, is a major concern due to the important role of symbiotic bacteria in many aspects of human health, such as shaping the immune system during development[1].

Darobactin A has a unique mechanism of action, binding to the BamA lateral gate in an antiparallel β-sheet conformation to inhibit outer membrane protein assembly[3]. It has been found to mimic a β-strand to inhibit outer membrane protein assembly, which is essential for Gram-negative bacteria[3].

The development of darobactin A as a potential antibiotic is promising, as it has an exceptional mechanism of action and a broad spectrum of activity against Gram-negative pathogens[2]. Modifications of individual amino acids of the darobactin heptapeptide have produced derivatives that show in vitro activity against pathogens prioritized by the World Health Organization (WHO) as critically important and often multi-resistant[2]. The derivative D69 has been found to have in vitro activity comparable to that of the currently best derivative D22, and the pharmacokinetics of the two most promising derivatives, D22 and D69, have been analyzed using the in-vitro-ADMET-model[2].

The total synthesis of darobactin A has been accomplished in a convergent fashion with a longest linear sequence of 16 steps from d-Garner's aldehyde and l-serine[5]. Scalable routes toward three non-canonical amino acids were developed to enable the synthesis, and the closure of the bismacrocycle was realized through sequential, halogen-selective Larock indole syntheses[5].

Overall, darobactin A is a promising candidate for the development of new, resistance-breaking antibiotics, and its unique mechanism of action and broad spectrum of activity make it a potential solution to the growing problem of antibiotic resistance[1][2][3].

Citations:

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188312/

[2] https://www.dzif.de/en/study-promising-new-antibiotic-darobactin-reinforces-its-potential

[3] https://www.nature.com/articles/s41586-021-03455-w

[4] https://en.wikipedia.org/wiki/Darobactin

[5] https://pubmed.ncbi.nlm.nih.gov/35900216/