ABSTRACT
We designed a few polymyxin derivatives which exhibit broad-spectrum antimicrobial activity. Lead compound P1 could disrupt bacterial membranes rapidly without developing resistance, inhibit biofilms formed by E. coli, and exhibit excellent in vivo activity in an MRSA-infected thigh burden mouse model.
Subject(s)
Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Polymyxins/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Biofilms/drug effects , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Conformation , Polymyxins/chemical synthesis , Polymyxins/chemistryABSTRACT
A new class of peptidomimetics termed as "γ-AApeptides" was recently developed by our group. Similar to other peptidomimetics, γ-AApeptides are resistant to proteolytic degradation, and possess limitless potential to introduce chemically diverse functional groups. γ-AApeptides have shown great promise in biomedical applications. In this article, we will review a few examples of γ-AApeptides with biological potential. Certain γ-AApeptides can permeate cell membranes and therefore they can be used as potential drug carrier. γ-AApeptides can also bind to HIV RNA with high specificity and affinity, suggesting their potential application as anti-HIV agents. Moreover, they can mimic host-defense peptides and display potent and broad-spectrum activity towards a range of drug-resistant bacterial pathogens. They are also potential anti-cancer agents. For instance, they have shown great promise in targeted imaging of tumor in mouse model, and they are also capable of disrupting p53/DNA interactions, and thus antagonize STAT3 signaling pathway. Recently, from combinatorial screening, γ-AApeptides are identified to inhibit Aß peptide aggregation, and thus they can be developed into potential anti- Alzheimer's disease agent.
Subject(s)
Peptidomimetics/chemistry , Peptidomimetics/pharmacology , Amyloid beta-Peptides/metabolism , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Peptide Fragments/metabolism , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Peptidomimetics/chemical synthesis , Protein Conformation, alpha-Helical , Protein Multimerization/drug effectsABSTRACT
There is considerable interest in the development of antimicrobial polymers including dendrimers due to the ease of synthesis and low manufacturing cost compared to host defense peptides (HDPs). Herein, a new class of nanomaterials-lipidated amphiphilic dendrimers-is presented that mimic the antibacterial mechanism of HDPs by compromising bacterial cell membranes. Unlike conventional dendrimers that are prepared generation by generation symmetrically with molecular weight distribution, these lipidated dendrimers are prepared on the solid phase with a hanging lipid tail and precisely controlled structure. It is shown through rational design that these lipidated dendrimers display potent and selective antimicrobial activity against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. In addition to antibacterial activity against planktonic bacteria, these dendrimers are also shown to inhibit bacterial biofilms effectively. This class of dendrimers as a new class of biomaterials may lead to a useful generation of antibiotic agents with practical applications.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Dendrimers/chemistry , Gram-Negative Bacteria/drug effects , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
With an increase of resistance in bacteria there is an urgent need for alternative treatment methods that could complement conventional antibiotics. In the past two decades, focus has been drawn to Host Defense Peptides (HDPs) as potential antibiotic agents. Herein we reported our studies on the development of lipidated α/α-AA heterogeneous peptides as a new class of HDP mimetics. These compounds showed potent antimicrobial activity toward both Gram-positive and Gram-negative bacteria, and they also displayed excellent selectivity as they only exhibited limited hemolytic activity. The fluorescence microscopy suggested that the mechanism of action of these heterogeneous peptides is bacterial membrane disruption, which is believed to be the major reason why it is difficult for bacteria to develop resistance. The subsequent time kill studies suggested that these compounds could rapidly eradicate bacteria. Moreover, this class of compounds could also effectively clear biofilms formed by both Gram-positive and Gram-negative bacteria. These findings suggested that lipidated α/α-AA heterogeneous peptides, as a new class of peptidomimetics, are promising antibiotic agents combating antibiotic resistance.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antimicrobial Cationic Peptides/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antimicrobial Cationic Peptides/chemical synthesis , Antimicrobial Cationic Peptides/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Microscopy, Fluorescence , Molecular Structure , Structure-Activity RelationshipABSTRACT
Quinoline compounds have been extensively explored as anti-malaria and anti-cancer agents for decades and show profound functional bioactivities, however, the studies of these compounds in other medicinal fields have lagged dramatically. In this study, we report the development of a series of facilely accessible quinoline derivatives that display potent antibacterial activity against a panel of multidrug-resistant Gram-positive bacterial strains, especially C. difficile. We also demonstrated that these molecules are effective in vivo against C. difficile. These results revealed that these types of quinoline compounds could serve as prototypes for the development of an appealing class of antibiotic agents used to combat Gram-positive drug-resistant bacterial strains, including C. difficile.
Subject(s)
Anti-Bacterial Agents/chemistry , Quinolines/chemistry , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cell Line , Cell Survival/drug effects , Clostridioides difficile/drug effects , Clostridium Infections/drug therapy , Clostridium Infections/pathology , Clostridium Infections/veterinary , Drug Resistance, Bacterial/drug effects , Female , Gram-Positive Bacteria/drug effects , Humans , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Quinolines/pharmacology , Quinolines/therapeutic use , Structure-Activity RelationshipABSTRACT
Antibiotic resistance is one of the biggest threats to public health, and new antibacterial agents hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Utilizing dimerization strategy, we rationally designed and efficiently synthesized a new series of small molecule dimeric lysine alkylamides as mimics of AMPs. Evaluation of these mimics against a panel of Gram-positive and Gram-negative bacteria including MDR strains was performed, and a broad-spectrum and potent compound 3d was identified. This compound displayed high specificity toward bacteria over mammalian cell. Time-kill kinetics and mechanistic studies suggest that compound 3d quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. In addition, lead compound 3d could inhibit biofilm formation and did not develop drug resistance in S. aureus and E. coli over 14 passages. These results suggested that dimeric lysine nonylamide has immense potential as a new type of novel small molecular agent to combat antibiotic resistance.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Lysine/analogs & derivatives , Biofilms/drug effects , Cell Membrane Permeability/drug effects , Drug Design , Drug Resistance, Multiple, Bacterial/drug effects , Escherichia coli/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hemolysis/drug effects , Humans , Microbial Sensitivity Tests , Staphylococcus aureus/drug effectsABSTRACT
Identification of molecular ligands that recognize peptides or proteins is significant but poses a fundamental challenge in chemical biology and biomedical sciences. Development of cyclic peptidomimetic library is scarce, and thus discovery of cyclic peptidomimetic ligands for protein targets is rare. Herein we report the unprecedented one-bead-two-compound (OBTC) combinatorial library based on a novel class of the macrocyclic peptidomimetics γ-AApeptides. In the library, we utilized the coding peptide tags synthesized with Dde-protected α-amino acids, which were orthogonal to solid phase synthesis of γ-AApeptides. Employing the thioether linkage, the desired macrocyclic γ-AApeptides were found to be effective for ligand identification. Screening the library against the receptor tyrosine kinase EphA2 led to the discovery of one lead compound that tightly bound to EphA2 (Kd = 81 nM) and potently antagonized EphA2-mediated signaling. This new approach of macrocyclic peptidomimetic library may lead to a novel platform for biomacromolecular surface recognition and function modulation.
Subject(s)
Peptide Library , Peptides, Cyclic/pharmacology , Peptidomimetics/pharmacology , Receptor, EphA2/antagonists & inhibitors , Cell Line, Tumor , Cell Movement/drug effects , Enzyme Assays , Humans , Molecular Dynamics Simulation , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/metabolism , Peptidomimetics/chemical synthesis , Peptidomimetics/metabolism , Protein Binding , Receptor, EphA2/metabolism , Sulfides/chemical synthesis , Sulfides/metabolism , Sulfides/pharmacologyABSTRACT
Hydantoin (imidazolidinedione) derivatives such as nitrofurantoin are small molecules that have aroused considerable interest recently due to their low rate of bacterial resistance. However, their moderate antimicrobial activity may hamper their application combating antibiotic resistance in the long run. Herein, we report the design of bacterial membrane-active hydantoin derivatives, from which we identified compounds that show much more potent antimicrobial activity than nitrofurantoin against a panel of clinically relevant Gram-positive and Gram-negative bacterial strains. These compounds are able to act on bacterial membranes, analogous to natural host-defense peptides. Additionally, these hydantoin compounds not only kill bacterial pathogens rapidly but also prevent the development of methicillin-resistant Staphylococcus aureus (MRSA) bacterial resistance under the tested conditions. More intriguingly, the lead compound exhibited in vivo efficacy that is much superior to vancomycin by eradicating bacteria and suppressing inflammation caused by MRSA-induced pneumonia in a rat model, demonstrating its promising therapeutic potential.
Subject(s)
Anti-Bacterial Agents/pharmacology , Hydantoins/pharmacology , Animals , Cell Membrane/drug effects , Drug Resistance, Bacterial , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , RatsABSTRACT
We designed a class of small dimeric cyclic guanidine derivatives which display potent antibacterial activity against both multidrug-resistant Gram-negative and Gram-positive bacteria. They could compromise bacterial membranes without developing resistance, inhibit biofilms formed by E. coli, and exhibit excellent in vivo activity in the MRSA-infected thigh burden mouse model.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Guanidine/analogs & derivatives , Guanidine/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/therapeutic use , Cyclization , Dimerization , Escherichia coli Infections/drug therapy , Guanidine/therapeutic use , Humans , Mice , Microbial Sensitivity Tests , Staphylococcal Infections/drug therapyABSTRACT
The resistance developed by life-threatening bacteria toward conventional antibiotics has become a major concern in public health. To combat antibiotic resistance, there has been a significant interest in the development of antimicrobial cationic polymers due to the ease of synthesis and low manufacturing cost compared to host-defense peptides (HDPs). Herein, we report the design and synthesis of amphiphilic polycarbonates containing primary amino groups. These polymers exhibit potent antimicrobial activity and excellent selectivity to Gram-positive bacteria, including multidrug resistant pathogens. Fluorescence and TEM studies suggest that these polymers are likely to kill bacteria by disrupting bacterial membranes. These polymers also show low tendency to elicit resistance in bacteria. Their further development may lead to new antimicrobial agents combating drug-resistance.
Subject(s)
Anti-Infective Agents/pharmacology , Gram-Positive Bacteria/drug effects , Polycarboxylate Cement/pharmacology , Polymers/pharmacology , Anti-Infective Agents/chemistry , Humans , Microbial Sensitivity Tests , Polycarboxylate Cement/chemistry , Polymers/chemistryABSTRACT
The intrinsic drawbacks encountered in bioactive peptides in chemical biology and biomedical sciences have diverted research efforts to the development of sequence-specific peptidomimetics that are capable of mimicking the structure and function of peptides and proteins. Modifications in the backbone and/or the side chain of peptides have been explored to develop biomimetic molecular probes or drug leads for biologically important targets. To expand the family of oligomeric peptidomimetics to facilitate their further application, we recently developed a new class of peptidomimetics, AApeptides based on a chiral peptide nucleic acid backbone. AApeptides are resistant to proteolytic degradation and amenable to enormous chemical diversification. Moreover, they could mimic the primary structure of peptides and also fold into discrete secondary structure such as helices and turn-like structures. Furthermore, they have started to show promise in applications in material and biomedical sciences. Herein, we highlight the structural design and some function of AApeptides and present our perspective on their future development.
Subject(s)
Anti-Infective Agents/chemistry , Peptide Nucleic Acids/chemistry , Peptidomimetics/chemistry , Amino Acids/chemistry , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Benzyl Compounds/chemistry , Candida albicans/drug effects , Candida albicans/growth & development , Cyclization , Fluorenes/chemistry , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/growth & development , Microbial Sensitivity Tests , Peptide Nucleic Acids/chemical synthesis , Peptide Nucleic Acids/pharmacology , Peptidomimetics/chemical synthesis , Peptidomimetics/pharmacology , Protein Stability , Protein Structure, Secondary , Proteolysis , Solid-Phase Synthesis Techniques , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Amides/chemistry , Anti-Bacterial Agents/chemistry , Acylation , Amides/chemical synthesis , Amides/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Cell Line, Tumor , Dipeptides/chemical synthesis , Dipeptides/chemistry , Dipeptides/pharmacology , Drug Resistance, Multiple, Bacterial , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hemolysis , Humans , Male , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Oxidation-Reduction , Pneumonia, Staphylococcal/drug therapy , Pneumonia, Staphylococcal/microbiology , Rats, Wistar , Structure-Activity RelationshipABSTRACT
As one of the greatest threats facing the 21st century, antibiotic resistance is now a major public health concern. Host-defense peptides (HDPs) offer an alternative approach to combat emerging multi-drug-resistant bacteria. It is known that helical HDPs such as magainin 2 and its analogs adopt cationic amphipathic conformations upon interaction with bacterial membranes, leading to membrane disruption and subsequent bacterial cell death. We have previously shown that amphipathic sulfono-γ-AApeptides could mimic magainin 2 and exhibit bactericidal activity. In this article, we demonstrate for the first time that amphipathic helical 1:1 α/sulfono-γ-AA heterogeneous peptides, in which regular amino acids and sulfono-γ-AApeptide building blocks are alternatively present in a 1:1 pattern, display potent antibacterial activity against both Gram-positive and Gram-negative bacterial pathogens. Small angle X-ray scattering (SAXS) suggests that the lead sequences adopt defined helical structures. The subsequent studies including fluorescence microscopy and time-kill experiments indicate that these hybrid peptides exert antimicrobial activity by mimicking the mechanism of HDPs. Our findings may lead to the development of HDP-mimicking antimicrobial peptidomimetics that combat drug-resistant bacterial pathogens. In addition, our results also demonstrate the effective design of a new class of helical foldamer, which could be employed to interrogate other important biological targets such as protein-protein interactions in the future.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Hemolysis/drug effects , Peptide Fragments/chemistry , Peptide Fragments/pharmacology , Sulfones/chemistry , Anti-Bacterial Agents/chemistry , Humans , Microbial Sensitivity Tests , Microscopy, Fluorescence , Molecular Conformation , Peptidomimetics , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
One of the biggest challenges in developing microRNA (miRNA) based therapeutics is the method of delivery. Herein we report the design and synthesis of mPEG-poly(amino acid)s, which we used as a novel nanocarrier for the delivery of miRNA-139-5p. The PEG-poly(amino acid)s/miRNA-139-5p nanoparticle complex is more effective at suppressing tumor growth and migration in mice with colorectal cancer than when treated with miRNA-139-5p solution and blank nanoparticles individually. Our results suggest that PEG-poly(amino acid)s are a promising non-viral gene vector for the delivery of miRNAs to treat cancers.