Total Synthesis and Biological Assessment of Novel Albicidins Discovered by Mass Spectrometric Networking

Abstract

Natural products represent an important source of potential novel antimicrobial drug leads. Low production by microorganisms in cell culture often delays the structural elucidation or even prevents a timely discovery. Starting from the anti‐Gram‐negative antibacterial compound albicidin produced by Xanthomonas albilineans, we describe a bioactivity‐guided approach combined with non‐targeted tandem mass spectrometry and spectral (molecular) networking for the discovery of novel antimicrobial compounds. We report eight new natural albicidin derivatives, four of which bear a β‐methoxy cyanoalanine or β‐methoxy asparagine as the central α‐amino acid. We present the total synthesis of these albicidins, which facilitated the unambiguous determination of the (2 S,3 R)‐stereoconfiguration which is complemented by the assessment of the stereochemistry on antibacterial activity.

Extensive Structure–Activity Relationship Study of Albicidin's C‐Terminal Dipeptidic p‐Aminobenzoic Acid Moiety

“…[13] Based on our previous investigations [11] we first sought a viable replacement for the hydrolyticallyu nstable b-cyanoalanine as building block C. The noncanonical amino acid 2amino-3-(1H-1,2,3-triazol-4-yl)propanoic acid (azahistidine) appealed to us as as uitable substitute as it mimics the cyanoalanine and methoxy-asparagine moieties presenti nt he naturally occurring variants of albicidin (1). [14] Indeed, the synthetic variant 2 exhibited superior antibacterial activity against the tested E. coli, S. typhimurium, B. subtilis and M. luteus strains,a s well as an eight-fold highera ctivity against ciprofloxacin (CIP) sensitive K. pneumoniae (Supporting Information, Ta ble S1). Consequently,w eu sed azahistidine-albicidin 2 as at emplate structuref or the subsequent SAR study:T he first set of analogues (3-17)a rises from sequential deletiono ft he methoxy and hydroxy groups present in the C-terminal dipeptidic pABA moiety ( Table 1, green).…”

“…Previous findings have shown at olerance for iso-propoxy groups as methoxy-substitutes. [14,15] Therefore, we hoped that more hydrophobic alkoxy groups in building blocks Ea nd F might help boost activity.T ot est this hypothesis, the methoxy moietieso ft he parentc ompound 2 were successively replaced by ethoxy groups to produce synthetic analogues 18-20 (Table 1, blue). Althoughe ach of the three compoundsi nhibited DNA gyrase and showed high to very high activities throughout the series of tested pathogens-except for Klebsiella strains-the doubly substituted analogue 20 stands out ( Figure 2).…”

“…Possibly,t he deleterious effect caused by the Table 1. Assignment of the residuesf or albicidin analogues with sequential deletion of the substituents of the C-terminal dipeptidic moiety (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), sequential replacement of the methoxy groups with ethoxyg roups (18)(19)(20), sequentialr eplacement of the phenolic core structure with pyridines (21-23), andw ith replacement of the carboxylic acid groupw ith a sulfonic acid group( 24). All derivatives contain azahistidine as building block C. O ne could conclude that the hydroxy group in building block Fi s imperative, but ad irect comparison of 22,f or example, with the trisubstituted ands till active analogue 6,n egates that assumption and makes adversee lectronic effects and H-bonding interactions between the nitrogen atom of the pyridine and the adjacent carboxylg roup more likely.…”

Cystobactamid 507: Concise Synthesis, Mode of Action, and Optimization toward More Potent Antibiotics

“…Accordingly, the individual middle, C‐ and N‐terminal rings were prepared followed by the coupling of the constituents. We established brief and efficient synthetic pathways for novel as well as reported amino acids, which are also precursors of other NPs (Scheme S1). Compared to previous methods, the middle ring of 2 ( 20 ) was prepared in only four steps using catechol as a starting material.…”

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

“…Die Naturstoffe und ihre entsprechenden BGCs wurden unabhängig voneinander in zwei nichtverwandten Spezies, Cystobacter sp. [165] isolierte Analoga namens Coralmycin A/B gehçren, sowie zahlreiche natürliche und synthetische Albicidin-Analoga [166][167][168][169] beschrieben. Beide Stoffklassen zeigen ausgezeichnete Wirksamkeit im niedrigen mgmL À1 -Bereich nicht nur gegen Gram-positive,s ondern auch gegen Gram-negative Bakterien und sind auch in klinisch relevanten ESKAPE-Stämmen aktiv.E sw urden zahlreiche Vertreter beider Klassen synthetisiert, wodurch auch die Konfiguration der zentralen Aminosäure eindeutig bestimmt werden konnte.D ie verschiedenen Derivate unterscheiden sich im Aminosäure-Motiv,d en pABA-Substituenten und der N-terminalen Modifikation.…”