Recent antibacterial carbohydrate-based prodrugs, drugs and delivery systems to overcome antimicrobial resistance

Antibacterial Prodrugs to Overcome Bacterial Antimicrobial Resistance

“…In the last two years, efforts have been made to understand and counter isoniazid resistance mechanisms. In 2021, the design and synthesis of new ‘direct’ InhA inhibitors that did not require KatG activation were reported [ 16 ] and, also, a new potential isoniazid inactivation mechanism was disclosed [ 14 , 17 ]. Since acetylation is a well-known mechanism used by bacteria to modify drugs and drug targets, Arun et al [ 17 ] hypothesized that M. tuberculosis could adopt a similar mechanism to inactivate isoniazid.…”

“…Also, the formulation of cyclodextrin drug complexes has been studied for improvement of lipid encapsulation of hydrophobic drugs. Safari et al [ 14 , 18 ] reported the synthesis of INH-HB ( 2 , Figure 1 ), a hydrophobic isoniazid (INH) prodrug resulting from its coupling with 4-hydroxybenzaldehyde (HB). Moreover, prodrugs’ complexation with α, β, and γ-cyclodextrins was tested and β-cyclodextrin (β-CD, 3 , Figure 1 ), with a predicted formation of H-bonding interactions between its hydroxy groups and the pyridinic nitrogen atom of the prodrug, was found to be the most suitable for increasing INH-HB solubility in water; therefore, being then chosen for further liposome encapsulation.…”

“…The formation of biofilms exhibiting bacterial lectins LecA and LecB as key structural components, contributes the most to the pathogenicity of these bacteria. Thus, Meiers et al [ 14 , 22 ] reported the synthesis and mechanism of action of the first biofilm-targeted prodrugs obtained by linking P. aeruginosa lectin probes to antibiotic cargos through alanine-glycine-leucine-alanine (Ala-Gly-Leu-Ala) cleavable peptide linkers, as depicted in Figure 5 . Fluoroquinolone-based antibiotic cargos, namely aminopyrrolidine ( 9 , MIC = 0.027–0.054 µM, Figure 5 ) and aminomethylpyrrolidine ( 10 , MIC = 0.29–1.45 µM, Figure 5 ), are similar to the potent antibiotic ciprofloxacin ( 11 , MIC = 0.125–0.25 µM, Figure 5 ) in terms of structure and antibiotic profiles; however, these contain a primary amine that may play a crucial role in proteolysis.…”

“…Tobramycin (TOB, 29 , Figure 10 ), an aminoglycoside antibiotic, and azithromycin (AZM, 30 , Figure 10 ), belonging to the macrolide family of antibiotics, have demonstrated therapeutic effects in cystic fibrosis patients, which are particularly vulnerable to infections caused by P. aeruginosa biofilms. In this context, a human serum albumin (HSA)-coated dimeric prodrug-based nanoassembly (DPNA, 31 , Scheme 1 ) to deliver TOB and AZM was developed by Li et al [ 14 , 32 ], in 2023. This nanocomplex, named HSA@DPNA ( 32 , Scheme 1 ), was obtained by insertion of pH-sensitive citraconic amide bonds between the two drugs, and exhibited stability under physiological conditions ( Scheme 1 ).…”

“…Hence, in addition to the carbohydrate-based prodrugs recently reviewed [ 14 ], we now aim at presenting the most recent findings on all chemical entities known to act as antibacterial prodrug agents reported from 2021 to 2023.…”