Overcoming AlbD Protease Resistance and Improving Potency: Synthesis and Bioactivity of Antibacterial Albicidin Analogues with Amide Bond Isosteres

Abstract

Albicidin is a potent antibacterial oligoaromatic peptide that is susceptible to the protease AlbD, a resistance factor. This potentially restricts the use of albicidin as a drug. To overcome this obstacle, we synthesized and evaluated six analogues with isosteric replacement of the key amide link. Protease stability was established while maintaining the antibacterial activity, including three analogues with up to eight times higher activity compared with the natural albicidin.

Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin

“…Importantly when considering eventual clinical use, these derivatives also demonstrated a good safety profile and efficacy in animal infection models using E. coli 26 . Albicidin resistance factors AlbA [27][28][29] , AlbD [30][31][32] and AlbG 20,33,34 were previously characterized by us and others. Structurally related gyrase inhibitors, cystobactamides, were also described in myxobacteria 35 .…”

Peptidomimetics: An Overview of Recent Medicinal Chemistry Efforts toward the Discovery of Novel Small Molecule Inhibitors

“…Antibacterial Peptidomimetics Derived from Natural Compounds. Very recently, Kleebauer et al 85 synthesized a series of six analogues 39a−39f of albicidin (37, Figure 15), a natural oligoaromatic peptide produced by Xanthomonas albilineans (X. albilineans). Albicidin ( 37) is known to inhibit the bacterial DNA gyrase.…”

Transcription activation by the resistance protein AlbA as a tool to evaluate derivatives of the antibiotic albicidin

“…The broad activity spectrum and its unique gyrase binding mode make albicidin an attractive lead for pharmaceutical development, despite several known (auto-)resistance mechanisms, 8,[22][23][24][25] which may be overcome by targeted engineering of the compound. 16,19,26 The resistance factor AlbA is a member of the MerR-like transcription regulator family, which typically reshape promoter DNA to induce transcription of downstream genes. 27 Many MerR-family transcription factors act as sensors of unfavourable conditions, such as metal-or oxidative stressresponse sensors and multi-drug responsive regulators, by employing a ligand-binding domain (LBD).…”

“…Efforts by us and others to optimize and develop albicidins or the structurally closely related cystobactamids 10 and coralmycins 11 have resulted in derivatives with increased stability and potent antibacterial activity against several ESKAPE 12 organisms, including Acinetobacter baumannii , Enterococcus faecium , Staphylococcus aureus and Pseudomonas aeruginosa . 13–19 Klebsiella species, on the other hand, have so far eluded most of our efforts and appear resistant against albicidin and most cystobactamids. 17 A specific albicidin binding protein has been described in K. oxytoca , 20,21 the MerR-family transcription regulator AlbA, which is at least partially responsible for the resistance.…”

“…The broad activity spectrum and its unique gyrase binding mode make albicidin an attractive lead for pharmaceutical development, despite several known (auto-)resistance mechanisms, 8,22–25 which may be overcome by targeted engineering of the compound. 16,19,26…”