Small Antimicrobial Agents Based on Acylated Reduced Amide Scaffold

Abstract

Prevalence of drug-resistant bacteria has emerged to be one of the greatest threats in the 21st century. Herein, we report the development of a series of small molecular antibacterial agents that are based on the acylated reduced amide scaffold. These molecules display good potency against a panel of multidrug-resistant Gram-positive and Gram-negative bacterial strains. Meanwhile, they also effectively inhibit the biofilm formation. Mechanistic studies suggest that these compounds kill bacteria by compromising bacterial membranes, a mechanism analogous to that of host-defense peptides (HDPs). The mechanism is further supported by the fact that the lead compounds do not induce resistance in MRSA bacteria even after 14 passages. Lastly, we also demonstrate that these molecules have therapeutic potential by preventing inflammation caused by MRSA induced pneumonia in a rat model. This class of compounds could lead to an appealing class of antibiotic agents combating drug-resistant bacterial strains.

Novel bis-cyclic guanidines as potent membrane-active antibacterial agents with therapeutic potential

“…To this end, a new series of bis-cyclic guanidine compounds (MW 600‒900 Da) were synthesized (Figure 2), and tested against a panel of multidrug resistant bacteria (Table 1). 16 As expected, some compounds showed exceptional in vitro and in vivo activity. When R 1 was kept as the phenyl group and R 2 was just proton (no substituent), no activity was detected for 1 and 2 with aliphatic (C 4 H 8 ) or aromatic ( m -phenylene) linker under the tested condition.…”

“…Such mechanisms also confer HDPs with broad-spectrum bactericidal activity. 4, 16 It should be noted that some HDPs do have defined intracellular targets besides their membrane- disruptive activity, nonetheless, these combined mechanisms of actions could indeed further synergize their antimicrobial activity. 13 Despite enthusiasm, there are obstacles associated with antibiotic HDPs and HDP-mimicking oligomeric peptidomimetics, 17–19 including difficulty in scale-up, low cost-effectiveness, potential immunogenicity and systematic toxicity.…”

“…Therefore, recently there has been considerable interest in the search of small molecules which mimic mechanism of action of HDPs. 16, 20–22 …”

Membrane-Active Hydantoin Derivatives as Antibiotic Agents

“…Our previous findings also indicated that cationic peptidomimetics with lipidation could kill bacteria with greater potency by disrupting bacterial membranes. 41–46 Thus, we hypothesized that hydantoin compounds bearing cationic groups and lipid tails (Figure 2, D2) would be membrane active, similar to the mechanism of action of HDPs. As such, they could interact with bacterial membranes and kill bacterial pathogens through bacterial membrane disruption.…”

Modulation of lipid membrane structural and mechanical properties by a peptidomimetic derived from reduced amide scaffold

“…We have recently developed a library of small compounds based on the reduced amide scaffold (Fig. 1) [20]. All compounds share the same backbone.…”