Synthesis and antibacterial activities of baulamycin A inspired derivatives.

SbnE is an essential enzyme for staphyloferrin B biosynthesis in Staphylococcus aureus. An earlier study showed that natural product baulamycin A has in vitro inhibitory activity against SbnE and antibacterial potency. A SAR study with analogues of baulamycin A was conducted to identify potent inhibitors of SbnE and/or effective antibiotics against MRSA. The results show that selected analogues, including 11, 18, 21, 24a, 24c, 24m and 24n, exhibit single-digit micromolar inhibitory potencies against SbnE (IC50s = 1.81-8.94 µM) and 11, 24m, 24n possess significant activities against both SbnE (IC50s = 4.12-6.12 µM) and bacteria (MICs = 4-32 µg/mL). Biological investigations revealed that these substances possess potent cell wall disruptive activities and that they inhibit siderophore production in MRSA. Among the selected analogues, 7 has excellent antibiotic activities both gram-positive and -negative bacteria (0.5-4 µg/mL). Moreover, these analogues significantly impede biofilm formation in a concentration-dependent manner. Taken together, the results of the investigation provide valuable insight into the nature of novel baulamycin A analogues that have potential efficacy against MRSA owing to their membrane damaging activity and/or inhibitory efficacy against siderophore production.

Total Syntheses of Fimsbactin A and B and Their Stereoisomers to Probe the Stereoselectivity of the Fimsbactin Uptake Machinery in Acinetobacter baumannii.

The stereoselective synthesis of fimsbactin A, a siderophore of the human pathogen Acinetobacter baumannii, was established. Based on this synthetic route, various fimsbactin stereoisomeric analogues were generated and tested for their iron delivery activity for A. baumannii. This investigation revealed that the fimsbactin uptake machinery in this bacterium was indeed highly stereoselective in substrate recognition.

Synthesis and Characterization of Anguibactin To Reveal Its Competence To Function as a Thermally Stable Surrogate Siderophore for a Gram-Negative Pathogen, Acinetobacter baumannii.

Total synthesis of anguibactin was accomplished for the first time, and the following biochemical characterizations allowed for the determination of its Fe(III) binding mode as well as the demonstration of its iron delivery capability for Acinetobacter baumannii. These properties, in addition to the thermal stability over acinetobactin, render anguibactin as a competent surrogate siderophore that can be useful for the future development of a siderophore-based antibiotic delivery system against A. baumannii.