Highly Antibacterial Active Aminoacyl Penicillin Conjugates with Acylated Bis-Catecholate Siderophores Based on Secondary Diamino Acids and Related Compounds

Abstract

New acylated bis-catecholates and 1,3-benzoxazine-2,4-dione derivatives based on secondary diamino acids (N-(aminoalkyl)glycines, N-aminopropyl-alanine, and N-aminopropyl-4-aminovaleric acid), on N-(aminoalkyl)aminomethyl benzoic acids, on N-(aminoalkyl)aminomethyl phenoxyacetic acids, or on 3,5-diaminobenzoic acid were synthesized as artificial siderophores. The corresponding diamino acids were obtained from the diamines and oxocarboxylic acids by catalytic hydrogenation. The acylated bis-catecholates and 1,3-benzoxazine-2,4-diones were coupled with ampicillin or amoxicillin to new siderophore aminoacylpenicillin conjugates. These conjugates exhibited very strong antibacterial activity in vitro against Gram-negative bacterial pathogens including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Escherichia coli, Klebsiella pneumoniae, and Serratia marcescens. The ampicillin derivative 7b (HKI 9924154) and the corresponding amoxicillin derivative 8 (HKI 9924155) represent the most active compounds. The conjugates can use bacterial iron siderophore uptake routes to penetrate the Gram-negative outer membrane permeability barrier. This was demonstrated by assays with mutants deficient in components of the iron transport systems. New siderophore penicillin V conjugates with the siderophore component attached to the phenyl ring of penicillin V are inactive against these Gram-negative bacteria.

Lydiamycins A–D: Cyclodepsipetides with Antimycobacterial Properties

“…[24,25] For Bacillus subtilis ATCC 6633, Mycobacterium smegmatis SG 987 (HKI0056), M. aurum SB66, M. vaccae IMET 10670, and M. fortuitum B, minimal inhibitory concentrations (MIC) were determined according to the NCCLS guidelines using the microbroth dilution method. [26,27] For M. tuberculosis strains, inoculae of 0.2 mL of 5 10 8 cells mL À1 were suspended in tubes with 2 mL of liquid Shkolnikova medium (Middelbrook H9 medium supplemented with human serum and egg albumin) containing twofold serial dilutions of the compounds, from 100.0 to 0.195 mg mL À1 . After 14 days of incubation at 37 8C, the tubes were centrifuged for 15 min at 3000 rpm.…”

Lydiamycine A–D: Cyclodepsipeptide mit antimykobakteriellen Eigenschaften

“…[24,25] Für Bacillus subtilis ATCC 6633, Mycobacterium smegmatis SG 987 (HKI0056), Mycobacterium aurum SB66, Mycobacterium vaccae IMET 10670 und Mycobacterium fortuitum B. wurden die minimalen Hemmkonzentrationen (MIC) mit der "Micro-Broth"-Verdünnungsmethode entsprechend den Vorschriften des NCCLS bestimmt. [26,27] Anzucht der M.-tuberculosis-Stämme: Inokula von 0. …”

Iron Transport: Siderophores

“…This 'Trojan horse' concept led to the synthesis of a series of siderophore-antibiotics. [224][225][226] Given the growing resistance, for example, of Mycobacterium tuberculosis and certain strains of Pseudomonas against antibiotic drugs currently at hand, there is an urgent need for completely new classes of antibiotics. The above mentioned approach might turn out to be of importance in the battle against pathogenic microbes and deserves therefore further intensive investigations.…”