Nature-Inspired (di)Azine-Bridged Bisindole Alkaloids with Potent Antibacterial In Vitro and In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus

Abstract

Natural bisindole alkaloids such as Hyrtinadine A and Alocasin A, which are known to exhibit diverse bioactivities, provide promising chemical scaffolds for drug development. By optimizing the Masuda borylation–Suzuki coupling sequence, a library of various natural product-derived and non-natural (di)­azine-bridged bisindoles was created. While unsubstituted bisindoles were devoid of antibacterial activity, 5,5′-chloro derivatives were highly active against methicillin-resistant Staphylococcus aureus (MRSA) and further Gram-positive pathogens at minimal inhibitory concentrations ranging from 0.20 to 0.78 μM. These compounds showed strong bactericidal killing effects but only moderate cytotoxicity against human cell lines. Furthermore, the two front-runner compounds 4j and 4n exhibited potent in vivo efficacy against MRSA in a mouse wound infection model. Although structurally related bisindoles were reported to specifically target pyruvate kinase in MRSA, antibacterial activity of 4j and 4n is independent of pyruvate kinase. Rather, these compounds lead to bacterial membrane permeabilization and cellular efflux of low-molecular-weight molecules.

Marine Alkaloids: Compounds with In Vivo Activity and Chemical Synthesis

“…The antimicrobial activity of marine alkaloids was also reported in the study carried out by Rehberg et al [ 41 ] with methicillin-resistant Staphylococcus aureus . These authors observed significant reductions in the size and microbial counts in contaminated skin wounds of animals treated with either 3,3′-(pyrimidine-2,5-diyl)bis(5-chloro-1H-indole) ( 39 ) or 2,6-bis(5-chloro-1H-indol-3-yl)pyridine ( 40 ) after 12 days.…”

“…Other relevant synthetic alkaloids are 3,3′-(pyrimidine-2,5-diyl)bis(5-chloro-1H-indole) ( 39 ) and 2,6-bis(5-chloro-1H-indol-3-yl)pyridine ( 40 ) [ 41 ]. The synthesis of 3,3′-(pyrimidine-2,5-diyl)bis(5-chloro-1H-indole) ( Figure 12 A; compound 39 ) was possible with a one-pot reaction composed of three steps initiated with 5-chloro-3-iodoindole ( 102 ).…”

“… Schematic representation of 3,3′-(pyrimidine-2,5-diyl)bis(5-chloro-1H-indole) ( 39 ) ( A )and 2,6-bis(5-chloro-1H-indol-3-yl)pyridine ( 40 ) ( B ) syntheses (according to Rehberg et al [ 41 ]). …”

Bis-Indole Alkaloids Isolated from the Sponge Spongosorites calcicola Disrupt Cell Membranes of MRSA

“…Previous study indicated that Gram-positive bacteria are more susceptible than Gramnegative to the antibacterial activity of bis-indoles [21]. It had been postulated that the outer membrane composition of Gram-negative bacteria may restrict bis-indole interaction and permeability [21].…”

“…Another study reported that the antibacterial activity of three natural bis-indoles, isolated from the sponge Topsentia pachastrelloides was due to the inhibition of MRSA pyruvate kinase (PK), an enzyme involved in carbohydrate metabolism [18]. However, a study on synthetic analogues and modified derivatives of bis-indoles originally isolated from the medicinal plant Alocasia macrorrhiza and sponge Hyritos sp., suggested that the antibacterial activity of these bis-indole alkaloids against MRSA is independent of PK inhibition and is instead due to the disruption of the cell membrane [21].…”