Mimics Of Antimicrobial Peptides Research Articles

Regulation of Hydrophobic Structures of Antibacterial Guanidinium-Based Amphiphilic Polymers for Subcutaneous Implant Applications.

Antimicrobial peptide mimics have been used to kill bacteria and construct antibacterial materials. Precise design and construction of chemical structure are essential for easy access to highly effective antimicrobial peptide mimics. Herein, cationic guanidinium-based polymers (PGXs) with varying hydrophobic structures were synthesized to explore the structure and antibacterial activity relationship of antimicrobial peptide mimics and to construct antibacterial implants. The effect of the hydrophobic chemical structure, including carbon chain length and configuration, on the antimicrobial activities against both Escherichia coli and Staphylococcus aureus was investigated. The antibacterial activities of PGXs improved with increasing alkyl chain length, and PGXs with a straight-chain hydrophobic structure exhibited better bactericidal activities than those with cyclic alkane and aromatic hydrocarbon. Furthermore, PGXs grafted with poly(dimethylsiloxane) (PDMS-PGXs) showed a similar bactericidal change tendency of PGXs in solution. Additionally, the PDMS-PGXs showed potent antibiofilm performance in vitro, which can inhibit bacterial infection in vivo as subcutaneous implants. This study may propose a basis for the precise design and construction of antibacterial materials and provide a promising way of designing biomedical devices and implants with bacterial infection-combating activities.

Incorporating Ceragenins into Coatings Protects Peripherally Inserted Central Catheter Lines against Pathogen Colonization for Multiple Weeks.

Healthcare-acquired infections and multi-drug resistance in pathogens pose a major crisis for the healthcare industry. Novel antibiotics which are effective against resistant strains and unlikely to elicit strong resistance are sought after in these settings. We have previously developed synthetic mimics of ubiquitous antimicrobial peptides and have worked to apply a lead compound, CSA-131, to the crisis. We aimed to generate a system of CSA-131-containing coatings for medical devices that can be adjusted to match elution and compound load for various environments and establish their efficacy in preventing the growth of common pathogens in and around these devices. Peripherally inserted central catheter (PICC) lines were selected for our substrate in this work, and a polyurethane-based system was used to establish coatings for evaluation. Microbial challenges by methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans were performed and SEM was used to evaluate coating structure and colonization. The results indicate that selected coatings show activity against selected planktonic pathogens that extend between 16 and 33 days, with similar periods of biofilm prevention.

Long‐term and fast‐bactericidal activity of methacrylamide‐based copolymer for antibiofilm coatings and antibacterial wipes applications

AbstractBacterial‐related infections can be hazardous for human health and the surrounding environment. Traditional antibiotic‐based treatments for these infections are increasingly ineffective due to the emergence of antibiotic‐resistant bacteria. Antimicrobial peptide mimics have emerged as promising replacements owing to their potency against bacteria and lack of susceptibility to generate resistant cells. Thus, we synthesized a random copolymer, consisting of aminopropyl methacrylamide and benzyl methacrylamide (AB polymer) by random co‐polymerization that mimics host–defense antimicrobial peptides. For its use as a coating, the AB polymer is drop‐casted onto a cleaned glass substrate and tested for its antibacterial activity toward Escherichia coli and Staphylococcus aureus, wherein almost 99% of antibacterial activity was observed within 5 min. The prepared coating also possessed excellent longevity characteristics of up to 5 weeks. The AB polymer is also able to inhibit biofilm formation as well as disrupt a mature biofilm and can also be employed as an antibacterial wipe for cleaning bacterial contaminated surfaces. Mechanism study through SEM analysis showed that the AB polymer ruptures the bilayer membrane of both bacterial strains, thereby leading to pore formation causing cell death. Cell viability study depicted that 71% of the A549 lung carcinoma epithelial cells are viable compared to 80% on bare glass substrate. Thus, the synthesized AB polymer may be used in a variety of antibacterial applications directly in the form of solution (wipes) or forming a coating (drop casted/spray coated) for battling bacterial colonization.

Electrostatic and Covalent Binding of an Antibacterial Polymer to Hydroxyapatite for Protection against Escherichia coli Colonization.

Orthopedic-device-related infections are notorious for causing physical and psychological trauma to patients suffering from them. Traditional methods of treating these infections have relied heavily on antibiotics and are becoming ineffectual due to the rise of antibiotic-resistant bacteria. Mimics of antimicrobial peptides have emerged as exciting alternatives due to their favorable antibacterial properties and lack of propensity for generating resistant bacteria. In this study, the efficacy of an antibacterial polymer as a coating material for hydroxyapatite and glass surfaces, two materials with wide ranging application in orthopedics and the biomedical sciences, is demonstrated. Both physical and covalent modes of attachment of the polymer to these materials were explored. Polymer attachment to the material surfaces was confirmed via X-ray photoelectron spectroscopy and contact angle measurements. The modified surfaces exhibited significant antibacterial activity against the Gram-negative bacterium E. coli, and the activity was retained for a prolonged period on the surfaces of the covalently modified materials.

Antimicrobial Peptides Incorporating Halogenated Marine-Derived Amino Acid Substituents.

Small synthetic mimics of cationic antimicrobial peptides represent a promising class of compounds with leads in clinical development for the treatment of persistent microbial infections. The activity and selectivity of these compounds rely on a balance between hydrophobic and cationic components, and here, we explore the activity of 19 linear cationic tripeptides against five different pathogenic bacteria and fungi, including clinical isolates. The compounds incorporated modified hydrophobic amino acids inspired by motifs often found in bioactive marine secondary metabolites in combination with different cationic residues to probe the possibility of generating active compounds with improved safety profiles. Several of the compounds displayed high activity (low μM concentrations), comparable with the positive controls AMC-109, amoxicillin, and amphotericin B. A higher activity was observed against the fungal strains, and a low in vitro off-target toxicity was observed against erythrocytes and HeLa cells, thereby illustrating effective means for tuning the activity and selectivity of short antimicrobial peptides.

Biophysical investigations of antimicrobial peptide mimics for mechanistic studies.

With a relentless rise in the growth of antimicrobial resistance, much attention is being focused on Antimicrobial peptides (AMP) and the development of AMP mimicking agents to combat this nefarious issue. However lesser reports come up with adequate reasoning behind the driving force of the membrane perturbing nature. Here, we shall be discussing the two branches of AMP mimics, peptoids and small molecules. Further, we explore the mode of action behind the antimicrobial properties displayed by the library of peptoids and small molecule mimics. To address this big challenge of understanding how the membrane active compound behaves, each of the compounds were introduced to the liposomes, mimicking the bacterial model membranes, and their interactions was recorded using solid state nuclear magnetic resonance spectroscopy. We observe that each of the mimics interact with the liposome as the global shape of the vesicles gets deformed. Also we observed a definite interaction with the fatty acyl chain as changes in order parameters were observed with respect to that of pure lipids. To develop a thorough understanding of the pore forming abilities of these compounds, a fluorescent dye release studies was executed using both bacterial and mammalian model membranes. The calcein dye release test revealed that the small molecule mimics undergo a cooperative effect. For the peptoids investigated, the extent of release could be correlated with their antimicrobial activity as well as the toxicity data.

Investigation of tetrasubstituted heterocycles reveals hydantoins as a promising scaffold for development of novel antimicrobials with membranolytic properties

Mimics of antimicrobial peptides (AMPs) have been proposed as a promising class of antimicrobial agents. We report the analysis of five tetrasubstituted, cationic, amphipathic heterocycles as potential AMP mimics. The analysis showed that the heterocyclic scaffold had a strong influence on the haemolytic activity of the compounds, and the hydantoin scaffold was identified as a promising template for drug lead development. Subsequently, a total of 20 hydantoin derivatives were studied for their antimicrobial potency and haemolytic activity. We found 19 of these derivatives to have very low haemolytic toxicity and identified three lead structures, 2dA, 6cG, and 6dG with very promising broad-spectrum antimicrobial activity. Lead structure 6dG displayed minimum inhibitory concentration (MIC) values as low as 1 μg/mL against Gram-positive bacteria and 4–16 μg/mL against Gram-negative bacteria. Initial mode of action (MoA) studies performed on the amine derivative 6cG, utilizing a luciferase-based biosensor assay, suggested a strong membrane disrupting effect on the outer and inner membrane of Escherichia coli. Our findings show that the physical properties and structural arrangement induced by the heterocyclic scaffolds are important factors in the design of AMP mimics.

Combating drug-resistant bacteria with sulfonium cationic poly(methionine).

antibiotic resistance and drug-resistant bacterial infections pose significant threats to public health. Antimicrobial peptides (AMPs) are a promising candidate for related-infection therapy, but their clinical application is limited by their high synthesis cost and susceptibility to protease degradation. To address these issues, cationic poly(α-amino acid)s based on lysine have been developed as synthetic mimics of AMPs. In this study, we introduce a new class of cationic AMP synthetic mimics based on functional poly(methionine)s. We synthesized a series of sulfonium cationic poly(d,l-methionine)s with varying chain lengths via a convenient polymerization on α-amino acid thiocarboxyanhydride (α-NTA) using tert-butyl-benzylamine as the initiator, followed by alkylation with iodomethane. Our optimal methionine polymer demonstrated potent and broad-spectrum antibacterial activity against antibiotic-resistant bacteria, as well as excellent biocompatibility with mammalian cells and rapid bactericidal performance. Our findings suggest that sulfonium poly(methionine)s have the potential to address the challenge of drug-resistant bacterial infections.

Development of biaromatic core-linked antimicrobial peptide mimics: Substituent position significantly affects antibacterial activity and hemolytic toxicity

The development of bacterial resistance to the majority of clinically significant antimicrobials has made it more difficult to treat bacterial infections with conventional antibiotics. As part of ongoing research on antimicrobial peptide mimetics, a series of quaternary ammonium cationic compounds with various linkers were designed and synthesized, with some demonstrating high antibacterial activity against Gram-negative and Gram-positive bacteria. The structure-activity relationship study revealed that the spatial position of substituents had a significant impact on antibacterial activity and hemolytic toxicity. The best compound, 3e, has good antibacterial activity against Staphylococcus aureus [minimum inhibitory concentration (MIC = 1 μg/mL)] and the least hemolytic toxicity [hemolytic concentration (HC50 = 905 μg/mL)], is stable in mammalian body fluids, and rarely induces bacterial resistance. The mechanism study revealed that the membrane action mode may be its potential bactericidal mechanism, and it can effectively cause the accumulation of intracellular reactive oxygen species (ROS) for killing bacteria. Importantly, 3e can effectively reduce the load of methicillin-resistant Staphylococcus aureus (MRSA) in mouse skin and has a higher in vivo bactericidal efficiency than vancomycin. These findings highlight the significance of divergent linkers in quaternary ammonium cations as antimicrobial peptide mimics and the potential of these cations to treat bacterial infections.

The Anti-Amoebic Activity of a Peptidomimetic against Acanthamoeba castellanii.

Acanthamoeba is a free-living protozoan known to cause keratitis most commonly, especially among contact lens wearers. Treatment of Acanthamoeba keratitis is challenging as Acanthamoeba can encyst from the active form, a trophozoite, into a hibernating cyst that is refractory to antibiotics and difficult to kill; therefore, there is a need for more effective anti-amoebic strategies. In this study, we have evaluated the anti-amoebic activity of the antimicrobial peptide mimic RK-758 against Acanthamoeba castellanii. RK-758 peptidomimetic was subjected to biological assays to investigate its amoebicidal, amoebistatic, anti-encystation, and anti-excystation effects on A. castellanii. The anti-amoebic activity of the peptide mimic RK-758 was compared with chlorhexidine against the Acanthamoeba castellanii ATCC30868 and Acanthamoeba castellanii 044 (a clinical strain) with the concentrations of both ranging from 125 µM down to 7.81 µM. All experiments were performed in duplicate with three independent replicates. The data were represented as mean ± SE and analysed using a two-sample t-test and two-tailed distributions. A p < 0.05 was considered statistically significant. The peptidomimetic RK-758 had anti-Acanthamoeba activity against both trophozoites and cysts in a dose-dependent manner. The RK-758 had amoebicidal and growth inhibitory activities of ≥50% at a concentration between 125 µM and 15.6 µM against the trophozoites of both Acanthamoeba strains. Inhibitory effects on the cyst formation and trophozoite re-emergence from cysts were noted at similar concentrations. Chlorhexidine had 50% activity at 7.81 µM and above against the trophozoites and cysts of both strains. In the haemolysis assay, the RK-758 lysed horse RBCs at concentrations greater than 50 µM whereas lysis occurred at concentrations greater than 125 µM for the chlorhexidine. The peptidomimetic RK-758, therefore, has activity against both the trophozoite and cyst forms of Acanthamoeba and has the potential to be further developed as an anti-microbial agent against Acanthamoeba. RK-758 may also have use as an anti-amoebic disinfectant in contact lens solutions.

N-Arylimidazoliums as Highly Selective Biomimetic Antimicrobial Agents.

Antibiotic resistance has become one of the greatest health threats in the world. In this study, a charge-dispersed dimerization strategy is described for the antimicrobial peptide (AMP) mimics via a tunable cationic charge to improve the selectivity between prokaryotic microbes and eukaryotic cells. This strategy is demonstrated with a series of charge-dispersed AMP mimics based on N-arylimidazolium skeletons. These N-arylimidazolium AMP mimics show potent antibacterial activity against strains along with a low rate of drug resistance, good hemocompatibility, and low cytotoxicity. In addition to the elimination of planktonic bacteria, N-arylimidazolium AMP mimics can also inhibit biofilm formation and destroy the established biofilm. More importantly, methicillin-resistant Staphylococcus aureus (MRSA)-induced lung-infected mice can be effectively treated by the intravenous administration of N-arylimidazolium AMP mimic, which enable the design of N-arylimidazolium AMP mimics to offer an alternative avenue to eradicate drug-resistant bacterial infection.

Evaluation of the Antimicrobial Activity in Host-Mimicking Media and In Vivo Toxicity of Antimicrobial Polymers as Functional Mimics of AMPs.

Activity tests for synthetic antimicrobial compounds are often limited to the minimal inhibitory concentration assay using standard media and bacterial strains. In this study, a family of acrylamide copolymers that act as synthetic mimics of antimicrobial peptides were synthesized and shown to have a disruptive effect on bacterial membranes and structural integrity through microscopy techniques and membrane polarization experiments. The polymers were tested for their antimicrobial properties using media that mimic clinically relevant conditions. Additionally, their activity was compared in two different strains of the Gram-positive bacterium Staphylococcus aureus and the Gram-negative bacterium Pseudomonas aeruginosa. We showed that the medium composition can have an important influence on the polymer activity as there was a considerable reduction in minimal inhibitory concentrations against S. aureus grown in synthetic wound fluid (SWF), and against P. aeruginosa grown in synthetic cystic fibrosis sputum media (SCFM), compared to the concentrations in standard testing media. In contrast, we observed a complete loss of activity against P. aeruginosa in the serum-containing SWF. Finally, we made use of an emerging invertebrate in vivo model, using Galleria mellonella larvae, to assess toxicity of the polymeric antimicrobials, showing a good correlation with cell line toxicity measurements and demonstrating its potential in the evaluation of novel antimicrobial materials.

Design, synthesis, and biological evaluation of membrane-active honokiol derivatives as potent antibacterial agents

Infections caused by drug-resistant bacteria have emerged to be one of the greatest threats to global public health, and new antimicrobial agents with novel mechanisms of action hence are in an urgent need to combat bacterial resistance. Herein, we reported the design, synthesis, and antibacterial evaluation of novel honokiol derivatives as mimics of antimicrobial peptides (AMPs). These mimics showed potent antimicrobial properties against Gram-positive bacteria. Among them, the most promising compound 13b exhibited excellent antibacterial activity, rapid bactericidal properties, avoidance of antibiotic resistance, and weak hemolytic and cytotoxic activities. In addition, compound 13b not only inhibited the biofilm formation but also destroy the preformed biofilm. Mechanism studies further revealed that compound 13b killed bacteria rapidly by interrupting the bacterial membrane. More intriguingly, compound 13b exhibited potent in vivo antibacterial efficacy in a mouse septicemia model induced by Staphylococcus aureus ATCC43300. These results highlight the potential of 13b to be used as therapeutic agents.

Antimicrobial Polymers of Linear and Bottlebrush Architecture: Probing the Membrane Interaction and Physicochemical Properties

Polymeric antimicrobial peptide mimics are a promising alternative for the future management of the daunting problems associated with antimicrobial resistance. However, the development of successful antimicrobial polymers (APs) requires careful control of factors such as amphiphilic balance, molecular weight, dispersity, sequence, and architecture. While most of the earlier developed APs focus on random linear copolymers, the development of APs with advanced architectures proves to be more potent. It is recently developed multivalent bottlebrush APs with improved antibacterial and hemocompatibility profiles, outperforming their linear counterparts. Understanding the rationale behind the outstanding biological activity of these newly developed antimicrobials is vital to further improving their performance. This work investigates the physicochemical properties governing the differences in activity between linear and bottlebrush architectures using various spectroscopic and microscopic techniques. Linear copolymers are more solvated, thermo-responsive, and possess facial amphiphilicity resulting in random aggregations when interacting with liposomes mimicking Escheria coli membranes. The bottlebrush copolymers adopt a more stable secondary conformation in aqueous solution in comparison to linear copolymers, conferring rapid and more specific binding mechanism to membranes. The advantageous physicochemical properties of the bottlebrush topology seem to be a determinant factor in the activity of these promising APs.

Antimicrobial Peptide Mimics for Clinical Use: Does Size Matter?

The search for efficient antimicrobial therapies that can alleviate suffering caused by infections from resistant bacteria is more urgent than ever before. Infections caused by multi-resistant pathogens represent a significant and increasing burden to healthcare and society and researcher are investigating new classes of bioactive compounds to slow down this development. Antimicrobial peptides from the innate immune system represent one promising class that offers a potential solution to the antibiotic resistance problem due to their mode of action on the microbial membranes. However, challenges associated with pharmacokinetics, bioavailability and off-target toxicity are slowing down the advancement and use of innate defensive peptides. Improving the therapeutic properties of these peptides is a strategy for reducing the clinical limitations and synthetic mimics of antimicrobial peptides are emerging as a promising class of molecules for a variety of antimicrobial applications. These compounds can be made significantly shorter while maintaining, or even improving antimicrobial properties, and several downsized synthetic mimics are now in clinical development for a range of infectious diseases. A variety of strategies can be employed to prepare these small compounds and this review describes the different compounds developed to date by adhering to a minimum pharmacophore based on an amphiphilic balance between cationic charge and hydrophobicity. These compounds can be made as small as dipeptides, circumventing the need for large compounds with elaborate three-dimensional structures to generate simplified and potent antimicrobial mimics for a range of medical applications. This review highlight key and recent development in the field of small antimicrobial peptide mimics as a promising class of antimicrobials, illustrating just how small you can go.

Bactericidal Activity of Ceragenin in Combination with Ceftazidime, Levofloxacin, Co-Trimoxazole, and Colistin against the Opportunistic Pathogen Stenotrophomonas maltophilia.

Background: Stenotrophomonas maltophilia (S. maltophilia) is an emerging opportunistic Gram-negative rod causing nosocomial infections predominantly in immunocompromised patients. Due to its broad intrinsic resistance to antibiotics, including carbapenems and the ability to form a biofilm, it is difficult to eradicate. Methods: In this study, the benefit of combined administration (potential synergism) and anti-biofilm activity of ceragenins: CSA-13, CSA-44, and CSA-131 (synthetic mimics of natural antimicrobial peptides) with ceftazidime, levofloxacin, co-trimoxazole and colistin against clinical strains of S. maltophilia were determined using MIC/MBC (minimum inhibitory concentration/minimum bactericidal concentration), killing assays and CV staining. Results: Obtained data indicate that the ceragenins exhibit strong activity against the tested strains of S. maltophilia grown in planktonic culture and as stationary biofilms. Moreover, with some strains, the synergy of ceragenins with conventional antibiotics was observed Conclusion: Our data suggest that ceragenins are promising agents for future development of new methods for treatment of infections caused by S. maltophilia, along with its potential use in combination with conventional antibiotics.

Cholic Acid-Based Antimicrobial Peptide Mimics as Antibacterial Agents.

There is a significant and urgent need for the development of novel antibacterial agents to tackle the increasing incidence of antibiotic resistance. Cholic acid-based small molecular antimicrobial peptide mimics are reported as potential new leads to treat bacterial infection. Here, we describe the design, synthesis and biological evaluation of cholic acid-based small molecular antimicrobial peptide mimics. The synthesis of cholic acid analogues involves the attachment of a hydrophobic moiety at the carboxyl terminal of the cholic acid scaffold, followed by the installation of one to three amino acid residues on the hydroxyl groups present on the cholic acid scaffold. Structure–activity relationship studies suggest that the tryptophan moiety is important for high antibacterial activity. Moreover, a minimum of +2 charge is also important for antimicrobial activity. In particular, analogues containing lysine-like residues showed the highest antibacterial potency against Gram-positive S. aureus. All di-substituted analogues possess high antimicrobial activity against both Gram-positive S. aureus as well as Gram-negative E. coli and P. aeruginosa. Analogues 17c and 17d with a combination of these features were found to be the most potent in this study. These compounds were able to depolarise the bacterial membrane, suggesting that they are potential antimicrobial pore forming agents.

Stereochemical Effects on the Antimicrobial Properties of Tetrasubstituted 2,5-Diketopiperazines.

Antimicrobial drug resistance is a looming health crisis facing us in the modern era, and new drugs are urgently needed to combat this growing problem. Synthetic mimics of antimicrobial peptides have recently emerged as a promising class of compounds for the treatment of persistent microbial infections. In the current study, we investigate five cyclic N-alkylated amphiphilic 2,5-diketopiperazines against 15 different strains of bacteria and fungi, including drug-resistant clinical isolates. Several of the 2,5-diketopiperazines displayed activities similar or superior to antibiotics currently in clinical use, with activities coupled to both the cationic and hydrophobic substituents. All possible stereoisomers of the lead peptide were prepared, and the effects of stereochemistry and amphiphilicity were investigated via 1D and 2D NMR spectroscopy, solution dynamics, and membrane interaction modeling. Clear differences in solution structures and membrane interaction potentials explain the differences seen in the bioactivity and physicochemical properties of each stereoisomer.

An Antimicrobial Peptide-Mimetic Methacrylate Random Copolymer Induces Domain Formation in a Model Bacterial Membrane.

To address the emerging issue of drug-resistant bacteria, membrane-active synthetic polymers have been designed and developed to mimic host-defense antimicrobial peptides (AMPs) as antibiotic alternatives. In this study, we investigated the domain formation induced by synthetic polymer mimics of AMPs using model membranes to elucidate the biophysical principles that govern their membrane-active mechanisms. To that end, lipid vesicles mimicking Escherichia coli(E. coli) membrane were prepared using an 8:2 (molar ratio) mixture of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol), sodium salt (POPG). Our studies using differential scanning calorimetry (DSC) and fluorescence microscopy indicated that cationic amphiphilic methacrylate random copolymers induced the phase separation to form POPE- or POPG-rich domains. A rhodamine-labeled polymer also showed the binding to separated domains in the membrane. Based on these results, we propose the mechanism that the copolymers induce domain formation by clustering of anionic POPG lipids similar to natural AMPs. In addition, the time-course of polymer binding to the GUV membrane was sigmoidal, suggesting the positive feedback loop in the membrane binding. We also hypothesize that this cooperative binding of the polymer is driven by the domain formation. This study demonstrates the potential of the amphiphilic copolymers to modulate the lipid organization of cell membranes, which may provide a new strategy to design membrane-active antimicrobial agents.

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.