ABSTRACT
Acinetobacter baumannii causes a wide range of infections, including wound infections. Multidrug-resistant A. baumannii is a major healthcare concern and the development of novel treatments against these infections is needed. Fosmidomycin is a repurposed antimalarial drug targeting the non-mevalonate pathway, and several derivatives show activity toward A. baumannii. We evaluated the antimicrobial activity of CC366, a fosmidomycin prodrug, against a collection of A. baumannii strains, using various in vitro and in vivo models; emphasis was placed on the evaluation of its anti-biofilm activity. We also developed a 3D-printed wound dressing containing CC366, using melt electrowriting technology. Minimal inhibitory concentrations of CC366 ranged from 1 to 64 µg/mL, and CC366 showed good biofilm inhibitory and moderate biofilm eradicating activity in vitro. CC366 successfully eluted from a 3D-printed dressing, the dressings prevented the formation of A. baumannnii wound biofilms in vitro and reduced A. baumannii infection in an in vivo mouse model.
ABSTRACT
Fosmidomycin is a natural antibiotic with potent IspC (DXR, 1-deoxy-d-xylulose-5-phosphate reductoisomerase) inhibitory activity. This enzyme catalyzes the first committed step of the non-mevalonate isoprenoid biosynthesis pathway, which is essential in most bacteria, including A. baumanii and M. tuberculosis, and apicomplexan parasites, including Plasmodium parasites. Mainly as a result of its high polarity, fosmidomycin displays suboptimal pharmacokinetic properties. Furthermore, fosmidomycin is inactive against A. baumannii and M. tuberculosis as a result of its inability to penetrate the bacterial cell wall. Temporarily masking the phosphonate moiety as a prodrug has the potential to solve both issues. We report on the expansion of the acyloxymethyl and alkoxycarbonyloxymethyl phosphonate ester prodrug series of a fosmidomycin surrogate. Prodrug promoieties were designed based on electronic, lipophilic and siderophoric properties. This investigation led to the discovery of derivatives with two-digit nanomolar and submicromolar IC50-values against P. falciparum and A. baumanii, respectively.
Subject(s)
Antimalarials , Folic Acid Antagonists , Malaria, Falciparum , Mycobacterium tuberculosis , Organophosphonates , Prodrugs , Tuberculosis , Humans , Antimalarials/pharmacology , Anti-Bacterial Agents/pharmacology , Prodrugs/pharmacologyABSTRACT
A series of N-alkoxy analogs of a l-leucine ethyl ester phosphonodiamidate prodrug of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. These compounds originate by merging a previously reported successful phosphonate derivatisation with favorable modifications of the hydroxamate moiety. None of the synthesized compounds showed enhanced activity against either P. falciparum or M. tuberculosis in comparison with the parent free hydroxamate analog.
Subject(s)
Antimalarials/chemistry , Antitubercular Agents/chemistry , Fosfomycin/analogs & derivatives , Organophosphonates/chemistry , Prodrugs/chemistry , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Cell Line , Cell Survival/drug effects , Fosfomycin/chemistry , Humans , Hydroxamic Acids/chemistry , Mycobacterium tuberculosis/drug effects , Plasmodium falciparum/drug effects , Prodrugs/chemical synthesis , Prodrugs/pharmacologyABSTRACT
A series of eleven double prodrug derivatives of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. A pivaloyloxymethyl (POM) phosphonate prodrug modification was combined with various prodrug derivatisations of the hydroxamate moiety. The majority of compounds showed activity comparable with or inferior to fosmidomycin against P. falciparum. N-benzyl substituted carbamate prodrug 6f was the most active antimalarial analog with an IC50 value of 0.64⯵M. Contrary to fosmidomycin and parent POM-prodrug 5, 2-nitrofuran and 2-nitrothiophene prodrugs 6i and 6j displayed promising antitubercular activities.
Subject(s)
Antimalarials/chemistry , Antitubercular Agents/chemistry , Mycobacterium tuberculosis/drug effects , Plasmodium falciparum/drug effects , Prodrugs/chemistry , Antimalarials/pharmacology , Antitubercular Agents/pharmacology , Carbamates/chemistry , Drug Evaluation, Preclinical/methods , Fosfomycin/analogs & derivatives , Fosfomycin/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Nitrofurans/chemistry , Prodrugs/pharmacology , Signal Transduction , Structure-Activity RelationshipABSTRACT
Fosmidomycin is a natural antibiotic with promising IspC (DXR, 1-deoxy-d-xylulose-5-phosphate reductoisomerase) inhibitory activity. This enzyme catalyzes the first committed step of the non-mevalonate isoprenoid biosynthesis pathway, which is essential in Plasmodium falciparum and Mycobacterium tuberculosis. Mainly as a result of its high polarity, fosmidomycin displays suboptimal pharmacokinetic properties. Furthermore, fosmidomycin is inactive against M. tuberculosis as a result of its inability to penetrate the bacterial cell wall. Temporarily masking the phosphonate moiety as a prodrug has the potential to solve both issues. We report the application of two amino acid based prodrug approaches on a fosmidomycin surrogate. Conversion of the phosphonate moiety into tyrosine-derived esters increases the in vitro activity against asexual blood stages of P. falciparum, while phosphonodiamidate prodrugs display promising antitubercular activities. Selected prodrugs were tested in vivo in a P. berghei malaria mouse model. These results indicate good in vivo antiplasmodial potential.
Subject(s)
Amino Acids/pharmacology , Antimalarials/pharmacology , Antitubercular Agents/pharmacology , Fosfomycin/analogs & derivatives , Prodrugs/pharmacology , Amino Acids/chemical synthesis , Amino Acids/toxicity , Animals , Antimalarials/chemical synthesis , Antimalarials/toxicity , Antitubercular Agents/chemical synthesis , Antitubercular Agents/toxicity , Cell Line , Female , Fosfomycin/chemical synthesis , Fosfomycin/pharmacology , Fosfomycin/toxicity , Humans , Mice , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Prodrugs/chemical synthesis , Prodrugs/toxicityABSTRACT
Two classes of prodrugs of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. To this end, a novel efficient synthesis route was developed involving a cross metathesis reaction as a key step. Alkoxyalkyl prodrugs show decent antimalarial activities, but acyloxybenzyl prodrugs proved to be the most interesting and show enhanced antimalarial and antitubercular activity. The most active antimalarial analogues show low nanomolar IC50 values.