Antibiotic discovery and development is challenging as chemical scaffolds of synthetic origin often lack the required pharmaceutical properties, and the discovery of novel ones from natural sources is tedious. Herein, we report the discovery of new cystobactamids with a significantly improved antibacterial profile in a detailed screening of myxobacterial producer strains. Some of these new derivatives display antibacterial activities in the low-μg mL range against Gram-negative pathogens, including clinical isolates of Klebsiella oxytoca, Pseudomonas aeruginosa, and fluoroquinolone-resistant Enterobacteriaceae, which were not observed for previously reported cystobactamids. Our findings provide structure-activity relationships and show how pathogen resistance can be overcome by natural scaffold diversity. The most promising derivative 861-2 was prepared by total synthesis, enabling further chemical optimization of this privileged scaffold.
Figure 1. Cystobactamid natural products, synthetic epimer 3a and the structural revision of cystobactamids 920-1 and 920-2 as presented in this work (the related peptide albicidin is also shown).Letter pubs.acs.org/OrgLett
An improved scalable synthesis of orthogonally functionalized methoxyaspartate, the chiral hinge region element in cystobactamids, is reported. This improvement sets the stage for the total synthesis of four new cystobactamids along with cystobactamid 861-2, whose antibacterial properties are determined and compared. The cyano derivative of cystobactamide 861-2 shows superior antibacterial activity against Gram-negative bacteria to any natural cystobactamide tested so far.T he group of cystobactamids was reported by Muller et al. in 2014 as part of a search for new secondary metabolites in Cystobacter sp. Cbv34. The extracts inhibited the growth of several Gram-negative and Gram-positive bacteria, and HPLCassisted bioactivity-guided screenings provided cystobactamids 919-1 (1) and 919-2 (2) as active compounds (Figure 1). 1 These oligoamides contain p-aminobenzoic acid building blocks and either an iso-β-methoxyasparagine or a β-methoxyasparagine unit. Later additional derivatives such as the cystobactamids 920-1 (3), 920-2 (4), and 862-1 (5) were reported that structurally differ in the D-and E-rings and the hinge region. 2 To date cystobactamid 862-1 is the most active natural member inhibiting several clinically relevant Gram-positive and Gramnegative strains (Acinetobacter baumannii: MIC = 0.5 μg/mL, Citrobacter f reundii: MIC = 0.06 μg/mL, carbapenem-resistant E. coli WT-III marRΔ74bp: MIC = 0.5 μg/mL, carbapenemresistant P. aeruginosa CRE: MIC = 1.0 μg/mL and Proteus vulgaris: MIC = 0.25 μg/mL) 2 by inhibiting bacterial type IIa topoisomerases. To date, three total syntheses of cystobactamids 861-2, 919-2, and 920-1 have been published by the Trauner group and by us. 2,3 These endeavors were essential to revise and
Cystobactamids belong to the group of arene‐based oligoamides that effectively inhibit bacterial type IIa topoisomerases. Cystobactamid 861‐2 is the most active member of these antibiotics. Most amide bonds present in the cystobactamids link benzoic acids with anilines and it was found that some of these amide bonds undergo chemical and enzymatic hydrolysis, especially the one linking ring C with ring D. This work reports on the chemical synthesis and biological evaluation of thirteen new cystobactamids that still contain the methoxyaspartate hinge. However, we exchanged selected amide bonds either by the urea or the triazole groups and modified ring A in the latter case. While hydrolytic stability could be improved with these structural substitutes, the high antibacterial potency of cystobactamid 861‐2 could only be preserved in selected cases. This includes derivatives, in which the urea group is positioned between rings A and B and where the triazole is found between rings C and D.
Die Entdeckung und Entwicklung neuer Antibiotika ist sehr anspruchsvoll, da synthetische Grundstrukturen häufig nichtd ie bençtigten pharmazeutischen Eigenschaften aufweisen und die Auffindung neuartiger Naturstoffe langwierig ist. Wirb eschreiben hier die Entdeckung neuer Cystobactamide mit signifikant verbesserten Bioaktivitätsprofilen, was durch die intensive Untersuchung myxobakterieller Produzentenstämme ermçglicht wurde.E inige dieser Derivate zeigen Aktivitäten im niedrigen mgml À1 -Bereichg egen klinische Isolate von Klebsiella oxytoca, Pseudomonas aeruginosa sowieF luorchinolon-resistente Enterobacteriaceae,w as im Fall bisher bekannter Cystobactamide nicht beobachtet wurde. Unsere Studien liefern Struktur-Aktivitäts-Beziehungen und verdeutlichen, wie Resistenzmechanismen durchn atürliche Strukturvielfalt außer Kraft gesetzt werden kçnnen. Das vielversprechendste Derivat 861-2 wurde totalsynthetischh ergestellt, was den Wegf üre ine chemische Optimierung der Grundstruktur ebnet.
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