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The identification of novel targets for antimicrobial agents is crucial for combating infectious diseases caused by evolving bacterial pathogens. Components of bacterial toxin–antitoxin (TA) systems have been recognized as promising therapeutic targets. These widespread genetic modules are usually composed of two genes that encode a toxic protein targeting an essential cellular process and an antitoxin that counteracts the activity of the toxin. Uncontrolled toxin expression may elicit a bactericidal effect, so they may be considered "intracellular molecular bombs" that can lead to elimination of their host cells. Based on the molecular nature of antitoxins and their mode of interaction with toxins, TA systems have been classified into six groups. The most prevalent are type II TA systems. Due to their ubiquity among clinical isolates of pathogenic bacteria and the essential processes targeted, they are promising candidates for the development of novel antimicrobial strategies. In this review, we describe the distribution of type II TA systems in clinically relevant human pathogens, examine how these systems could be developed as the targets for novel antibacterials, and discuss possible undesirable effects of such therapeutic intervention, such as the induction of persister cells, biofilm formation and toxicity to eukaryotic cells. [ABSTRACT FROM AUTHOR]

The overuse of antibiotics has led to a rise in infections caused by multidrug-resistant bacteria, resulting in a need for new antibacterial compounds with different modes of action. In this paper, we describe a new class of compounds called lipooligoureas, which are foldamer-based mimetics of antimicrobial lipopeptides. The lipooligoureas consist of an acyl chain connected to the N -terminus of an oligourea head group that exhibits a well-defined 2.5-helix secondary structure, which is further stabilized by the attachment of the lipophilic chain to the oligourea moiety. These compounds meet the established criteria for membranolytic compounds by possessing an amphiphilic structure that promotes the internalization and partitioning of the molecules into the lipid membrane. The presence of positively charged urea residues promotes electrostatic interactions with the negatively charged bacterial membrane. The subtle structural differences in oligourea head group influence the compounds' aggregation behavior, with the number and position of positively charged urea residues correlating with their aggregation ability. The biological activity of these compounds in inhibiting bacterial growth is correlated with their ability to aggregate, with stronger antibacterial properties exhibited by those that aggregate more easily. However, the concentration inhibiting bacterial growth is significantly lower than the critical aggregation concentration values, suggesting that the mechanism of action involves the monomeric forms of lipooligoureas. Nonetheless, a mechanism based on membrane-induced aggregation cannot be ruled out. The lipooligoureas exhibit higher activity towards Gram-positive bacteria than against Gram-negative bacteria, which is indicative of certain selectivity of these compounds. It is also demonstrated that lipooligoureas exhibit increased stability against proteolytic degradation in human blood serum. [Display omitted] • We demonstrate foldamer-based mimetics of lipopeptides, called lipooligoureas. • Lipooligoureas display antimicrobial activity and inhibit the growth of MRSA strains. • They show increased stability against proteolytic degradation in human blood serum. • Structural differences in oligourea moiety determine their aggregation behavior. • Aggregation ability correlates with antimicrobial activity. [ABSTRACT FROM AUTHOR]