Improvement of the antimicrobial potency, pharmacokinetic and pharmacodynamic properties of albicidin by incorporation of nitrogen atoms

Abstract

The worrysome development and spread of multidrug-resistant bacteria demands new antibacterial agents with strong bioactivities particularly against Gram−negative bacteria. Albicidins were recently structurally characterized as highly active antibacterial natural products...

Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin

“…3a and Extended Data Fig. 7 ) with features leading to improved pharmacological characteristics and nanomolar-range activity towards FQ-resistant pathogens 26 (a minimum inhibitory concentration (MIC) ≤ 0.016 µg ml −1 for E. coli; see also Table 1 and Extended Data Fig. 8 ).…”

“…In summary, our work provides the structural framework explaining multiple previous observations based solely on chemical synthesis and activity profiling. Albicidin derivatives, particularly of the Albi-1 or Albi-3 type, have already demonstrated safety and efficacy in animal infection models 26 . The α3/α3′ binding pocket is unique and does not overlap with any other known classes of topoisomerase inhibitors.…”

“…We have established synthetic routes for the parent compound 22 and multiple derivatives [23][24][25] , including ones with improved characteristics and nanomolar-range activity against Gram-negative bacteria such as E. coli, S. typhimurium and A. baumannii. 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.…”

Gene amplifications cause high-level resistance against albicidin in Gram-negative bacteria

“…The promising antibacterial peptide albicidin was first isolated as a phytotoxic compound from the plant-pathogenic bacterium Xanthomonas albilineans (6,7). Since then, albicidin (8)(9)(10) as well as the related compounds cystobactamids (11,12) and coralmycins (13,14) are undergoing development towards clinical use. Albicidin is active at nanomolar concentrations against a range of different Gram-positive and Gram-negative bacterial species, including Klebsiella aerogenes, Salmonella Typhimurium, Escherichia coli, as well as the ESKAPE pathogens Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterbacter spp..…”

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

“…9,40,41 aeruginosa. [13][14][15][16][17][18][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 specic 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.…”