Peripheral modifications of [Ψ[CH ₂ NH]Tpg ⁴ ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

Abstract

Significance In a quest for antibiotics that may display durable clinical lifetimes, analogs of the glycopeptide antibiotics, including vancomycin, have been designed that not only directly overcome the molecular basis of existing vancomycin resistance but also contain two added peripheral modifications that endow them with two additional independent mechanisms of actions not found in the parent antibiotics. It is shown that such peripherally and binding pocket-modified vancomycin analogs display little propensity for acquired resistance by vancomycin-resistant Enterococci and that both their antimicrobial potency and durability against such challenges follow trends (three > two > one mechanisms of action) that are now predictable.

A GenoChemetic strategy for derivatization of the violacein natural product scaffold

“…However, given the larger chemical space accessible by total synthesis compared to enzyme-catalysed biosynthesis, a combination of both synthetic routes (also known as semi-synthesis) to generate drug screening libraries has become increasingly common 7 . More recently, analogues of a 'last-resort' antibiotic vancomycin had been found to have >200-fold improvement of potency compared to vancomycin in resistant Enterococci strains 8 . In another study, the addition of a sterically unhindered primary amine group to a…”

The race for antimicrobials in the multidrug resistance era

“…Despite the loss of efficiency of most of these modified molecules due to the development of resistance, a recent report by Okano and collaborators highlighted the great potential that chemical modification still has to generate novel molecules with low risks of the emergence of resistance (Okano et al ., 2017). To illustrate this idea, the authors focus on vancomycin, a last‐line antibiotic in clinics.…”

“…This chemical modification served as a starting point for the introduction of further single peripheral modifications at the C‐terminus, which led to a battery of new and improved versions of vancomycin against a vancomycin‐resistant pathogen (VanA VRE). The incorporation of a quaternary ammonium salt bearing a tetradecyl substituent, called C14, resulted in an increase in the antimicrobial potency 10‐ or 1000‐fold higher than the vancomycin derivative or native vancomycin, respectively, a gain apparently related to membrane permeability as a second mode of action (Okano et al ., 2017). Another peripheral modification of the CBP‐vancomycin derivative, called C1 (quaternary ammonium salt bearing a methyl substituent), generated a new version, displaying three modes of action that cooperatively arrest the cell wall synthesis: (i) a pocket modification with affinity for both D ‐Ala‐ D ‐Ala and D ‐Ala‐ D ‐Lac bonds and the ability to inhibit the transpeptidase‐catalyzed cross‐linking; (ii) a CBP disaccharide modification that enables the direct inhibition of the transglycosylase reaction without the need to bind to D ‐Ala‐ D ‐Ala/ D ‐Ala‐ D ‐Lac; and (iii) the C1 quaternary ammonium salt C‐terminal modification responsible for membrane permeability.…”

“…Another peripheral modification of the CBP‐vancomycin derivative, called C1 (quaternary ammonium salt bearing a methyl substituent), generated a new version, displaying three modes of action that cooperatively arrest the cell wall synthesis: (i) a pocket modification with affinity for both D ‐Ala‐ D ‐Ala and D ‐Ala‐ D ‐Lac bonds and the ability to inhibit the transpeptidase‐catalyzed cross‐linking; (ii) a CBP disaccharide modification that enables the direct inhibition of the transglycosylase reaction without the need to bind to D ‐Ala‐ D ‐Ala/ D ‐Ala‐ D ‐Lac; and (iii) the C1 quaternary ammonium salt C‐terminal modification responsible for membrane permeability. The result is a modified vancomycin molecule with the most potent inhibition of cell wall synthesis and the most pronounced and potent induction of cell membrane permeability, of all the compounds examined to date, with up to 10 000‐fold more potency than the original vancomycin (Okano et al ., 2017). Furthermore, the fact that there were no changes in the susceptibility of diverse pathogenic bacteria to this new version of vancomycin after up to 50 days of experiments, indicated that the combination of the three different mechanisms of action complicates an otherwise easy evolution of pathogenic bacteria from sensitive to resistant.…”

Remodeling vancomycin yields a victory in the battle against bacteria

“…Recently, a significant advance in the battle against bacteria has been achieved. In PNAS, Okano et al (5) report the discovery of a new antibiotic that functions via three synergistic modes of action. Importantly, the ability of this agent to attack bacteria using multiple mechanisms dramatically slows the development of resistance.…”