Recently, a series of endo-type B polycyclic polyprenylated acylphloroglucinols (PPAP) derivatives with high antimicrobial activities were chemically synthesized. One of the derivatives, PPAP 23, which showed high antimicrobial activity and low cytotoxicity, was chosen for further investigation of its bactericidal profiles and mode of action. PPAP 23 showed a better efficacy in killing methicillin resistant Staphylococcus aureus (MRSA) and decreasing the metabolic activity of 5-day-old biofilm cells than vancomycin. Moreover, S. aureus did not appear to develop resistance against PPAP 23. The antimicrobial mechanism of PPAP 23 was investigated by RNA-seq combined with phenotypic and biochemical approaches. RNA-seq suggested that PPAP 23 signaled iron overload to the bacterial cells because genes involved in iron transport were downregulated and iron storage gene was upregulated by PPAP 23. PPAP 23 affected the membrane integrity but did not induce pore formation; it inhibited bacterial respiration. PPAP 23 preferentially inhibited Fe–S cluster enzymes; it has a mild iron chelating activity and supplementation of exogenous iron attenuated its antimicrobial activity. PPAP 23 was more effective in inhibiting the growth of S. aureus under iron-restricted condition. The crystal structure of a benzylated analog of PPAP 23 showed a highly defined octahedral coordination of three PPAP ligands around a Fe (3+) core. This suggests that PPAPs are generally capable of iron chelation and are able to form defined stable complexes. PPAP 23 was found to induce reactive oxygen species (ROS) and oxidative stress. Fluorescence microscopic analysis showed that PPAP 23 caused an enlargement of the bacterial cells, perturbed the membrane, and dislocated the nucleoid. Taken together, we postulate that PPAP 23 interacts with the cytoplasmic membrane with its hydrophobic pocket and interferes with the iron metabolism to exert its antimicrobial activity in Staphylococcus aureus.
In the past 20 years, peptide-based antibiotics, such as vancomycin, teicoplanin, and daptomycin, have often been considered as second-line antibiotics. However, in recent years, an increasing number of reports on vancomycin resistance in pathogens appeared, which forces researchers to find novel lead structures for potent new antibiotics. Herein, we report the total synthesis of a defined endo-type B PPAP library and their antibiotic activity against multiresistant S. aureus and various vancomycin-resistant Enterococci. Four new compounds that combine high activities and low cytotoxicity were identified, indicating that the PPAP core might become a new non-peptide-based lead structure in antibiotic research.
The nucleophilic Fe complex Bu4N[Fe(CO)3(NO)] (TBA[Fe]) catalyzes the direct intramolecular amination of aryl vinyl azides to give the corresponding indole derivatives in good to excellent yields.
The nucleophilic iron complex Bu4N[Fe(CO)3(NO)] (TBA[Fe]) is an active catalyst in C−H‐amination but also in proton‐transfer catalysis. Herein, we describe the successful use of this complex as a proton‐transfer catalyst in the cyclocondensation reaction between azides and ketones to the corresponding 1,2,3‐triazoles. Cross‐experiments indicate that the proton‐transfer catalysis is significantly faster than the nitrene‐transfer catalysis, which would lead to the C−H amination product. An example of a successful sequential Dimroth triazole–indoline synthesis to the corresponding triazole‐substituted indolines is presented.
In den vergangenen 20 Jahren wurden peptidbasierte Antibiotika wie Vancomycin, Teicoplanin oder Daptomycin als Reserveantibiotika betrachtet. In den letzten Jahren erschienen jedochvermehrt Berichte über Vancomycin-resistente Krankheitserreger,w as die Entwicklung neuartiger Leitstrukturen fürneue wirksame Antibiotika motivierte.Hier wird über die Totalsynthese einer definierten endo-Typ-B-PPAP-Bibliothek und deren antibiotische Aktivitätg egen multiresistente Staphylococcus-aureus-und diverse Vancomycin-resistente Enterococcus-Stämme berichtet. Es wurden vier neue Strukturen identifiziert, die zeigen, dass das PPAP-Grundgerüst eine neue nicht-peptidbasierte Leitstruktur in der Antibiotika-Forschung werden kçnnte,die sich durch die Kombination von hoher Aktivitätund geringer Zytotoxizitätauszeichnet.
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