Self-Assembly of Antimicrobial Peptoids Impacts Their Biological Effects on ESKAPE Bacterial Pathogens.

Antimicrobial peptides (AMPs) are promising pharmaceutical candidates for the prevention and treatment of infections caused by multidrug-resistant ESKAPE pathogens, which are responsible for the majority of hospital-acquired infections. Clinical translation of AMPs has been limited, in part by apparent toxicity on systemic dosing and by instability arising from susceptibility to proteolysis. Peptoids (sequence-specific oligo-N-substituted glycines) resist proteolytic digestion and thus are of value as AMP mimics. Only a few natural AMPs such as LL-37 and polymyxin self-assemble in solution; whether antimicrobial peptoids mimic these properties has been unknown. Here, we examine the antibacterial efficacy and dynamic self-assembly in aqueous media of eight peptoid mimics of cationic AMPs designed to self-assemble and two nonassembling controls. These amphipathic peptoids self-assembled in different ways, as determined by small-angle X-ray scattering; some adopt helical bundles, while others form core-shell ellipsoidal or worm-like micelles. Interestingly, many of these peptoid assemblies show promising antibacterial, antibiofilm activity in vitro in media, under host-mimicking conditions and antiabscess activity in vivo. While self-assembly correlated overall with antibacterial efficacy, this correlation was imperfect. Certain self-assembled morphologies seem better-suited for antibacterial activity. In particular, a peptoid exhibiting a high fraction of long, worm-like micelles showed reduced antibacterial, antibiofilm, and antiabscess activity against ESKAPE pathogens compared with peptoids that form ellipsoidal or bundled assemblies. This is the first report of self-assembling peptoid antibacterials with activity against in vivo biofilm-like infections relevant to clinical medicine.

Friends or enemies? The complicated relationship between Pseudomonas aeruginosa and Staphylococcus aureus.

Pseudomonas aeruginosa (Pa) and Staphylococcus aureus (Sa) are opportunistic pathogens that are most commonly co-isolated from chronic wounds and the sputum of cystic fibrosis patients. Over the last few years, there have been plenty of contrasting results from studies involving P. aeruginosa and S. aureus co-cultures. The general concept that P. aeruginosa outcompetes S. aureus has been challenged and there is more evidence now that they can co-exist. Nevertheless, it still remains difficult to mimic polymicrobial infections in vitro and in vivo. In this review, we discuss recent advances in regard to Pa-Sa molecular interactions, their physical responses, and in vitro and in vivo models. We believe it is important to optimize growth conditions in the laboratory, determine appropriate bacterial starting ratios, and consider environmental factors to study the co-existence of these two pathogens. Ideally, optimized growth media should reflect host-mimicking conditions with or without host cells that allow both bacteria to co-exist. To further identify mechanisms that could help to treat these complex infections, we propose to use relevant polymicrobial animal models. Ultimately, we briefly discuss how polymicrobial infections can increase antibiotic tolerance.