Derivatives of Ribosome-Inhibiting Antibiotic Chloramphenicol Inhibit the Biosynthesis of Bacterial Cell Wall

Abstract

Here, we describe the preparation and evaluation of α,β-unsaturated carbonyl derivatives of the bacterial translation inhibiting antibiotic chloramphenicol (CAM). Compared to the parent antibiotic, two compounds containing α,β-unsaturated ketones (1 and 4) displayed a broader spectrum of activity against a panel of Gram-positive pathogens with a minimum inhibitory concentration range of 2-32 μg/mL. Interestingly, unlike the parent CAM, these compounds do not inhibit bacterial translation. Microscopic evidence and metabolic labeling of a cell wall peptidoglycan suggested that compounds 1 and 4 caused extensive damage to the envelope of Staphylococcus aureus cells by inhibition of the early stage of cell wall peptidoglycan biosynthesis. Unlike the effect of membrane-disrupting antimicrobial cationic amphiphiles, these compounds did not rapidly permeabilize the bacterial membrane. Like the parent antibiotic CAM, compounds 1 and 4 had a bacteriostatic effect on S. aureus. Both compounds 1 and 4 were cytotoxic to immortalized nucleated mammalian cells; however, neither caused measurable membrane damage to mammalian red blood cells. These data suggest that the reported CAM-derived antimicrobial agents offer a new molecular scaffold for development of novel bacterial cell wall biosynthesis inhibiting antibiotics.

Fresh Molecular Concepts to Extend the Lifetimes of Old Antimicrobial Drugs

“…Since the primary and secondary alcohols of chloramphenicol are essential for binding to their ribosomal target we reasoned that it is unlikely that α‐dichloroacetamido‐ p ‐nitroacrylophenone is an inhibitor of bacterial translation and investigated its mode of action [64,65] . As expected, our in vitro translation experiments indicated that, unlike the parent antibiotic chloramphenicol, α‐dichloroacetamido‐ p ‐nitroacrylophenone is a poor inhibitor of translation [68] . Cell permeability experiments indicated that this chloramphenicol derivative does not rapidly increase membrane permeability of bacterial cells and were indicative of a bacteriostatic effect.…”

“…Transmission electron microscopy images of bacteria treated with α‐dichloroacetamido‐ p ‐nitroacrylophenone showed an extensive bacterial cell envelope damage. Metabolic labeling of S. aureus cells that were pre‐incubated with azido‐D‐alanine, which is incorporated into the cell wall peptidoglycan, indicated that unlike the parent chloramphenicol that inhibits protein translation, α‐dichloroacetamido‐ p ‐nitroacrylophenone inhibits an early stage of cell wall biosynthesis [68] …”

Recent Trends in Synthesis of Chloramphenicol New Derivatives

“…Zada et al described the preparation and evaluation of the α,β-unsaturated carbonyl derivatives of chloramphenicol ( 1 ) and derivative 42 for SAR studies [ 24 ]. The target compounds were synthesized starting from commercially available CAM ( 1 ), thiophenicol ( 44a ), or from the synthetic CAM analogs ( 45a – 47a ) ( Scheme 8 A).…”

Translational control of antibiotic resistance

“…Derivatization of chloramphenicol can also have a significant impact on which cellular process the drug will target. For example, chloramphenicol-derived enone and enal analogues have been shown to inhibit cell wall biosynthesis rather than translation [90]. Although these derivatives have a drastically different mechanism of action, they are still highly efficient in inhibiting bacterial growth and exhibit a significantly lower propensity for resistance formation than the parent molecule.…”