ABSTRACT
Peptides displaying antimicrobial properties are being regarded as useful tools to evade and combat antimicrobial resistance, a major public health challenge. Here we have addressed dendrimers, attractive molecules in pharmaceutical innovation and development displaying broad biological activity. Triazine-based dendrimers were fully synthesized in the solid phase, and their antimicrobial activity and some insights into their mechanisms of action were explored. Triazine is present in a large number of compounds with highly diverse biological targets with broad biological activities and could be an excellent branching unit to accommodate peptides. Our results show that the novel peptide dendrimers synthesized have remarkable antimicrobial activity against Gram-negative bacteria (E. coli and P. aeruginosa) and suggest that they may be useful in neutralizing the effect of efflux machinery on resistance.
Subject(s)
Dendrimers , Escherichia coli , Microbial Sensitivity Tests , Triazines , Dendrimers/chemistry , Dendrimers/chemical synthesis , Dendrimers/pharmacology , Triazines/chemistry , Triazines/pharmacology , Triazines/chemical synthesis , Escherichia coli/drug effects , Pseudomonas aeruginosa/drug effects , Antimicrobial Peptides/chemistry , Antimicrobial Peptides/pharmacology , Antimicrobial Peptides/chemical synthesis , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/chemical synthesis , Antimicrobial Cationic Peptides/pharmacology , Antimicrobial Cationic Peptides/chemistry , Antimicrobial Cationic Peptides/chemical synthesisABSTRACT
Antimicrobial peptides (AMPs) are essential elements of thehost defense system. Characterized by heterogenous structures and broad-spectrumaction, they are promising candidates for combating multidrug resistance. Thecombined use of AMPs with other antimicrobial agents provides a new arsenal ofdrugs with synergistic action, thereby overcoming the drawback of monotherapiesduring infections. AMPs kill microbes via pore formation, thus inhibitingintracellular functions. This mechanism of action by AMPs is an advantage overantibiotics as it hinders the development of drug resistance. The synergisticeffect of AMPs will allow the repurposing of conventional antimicrobials andenhance their clinical outcomes, reduce toxicity, and, most significantly,prevent the development of resistance. In this review, various synergies ofAMPs with antimicrobials and miscellaneous agents are discussed. The effect ofstructural diversity and chemical modification on AMP properties is firstaddressed and then different combinations that can lead to synergistic action,whether this combination is between AMPs and antimicrobials, or AMPs andmiscellaneous compounds, are attended. This review can serve as guidance whenredesigning and repurposing the use of AMPs in combination with other antimicrobialagents for enhanced clinical outcomes.
Subject(s)
Anti-Infective Agents , Communicable Diseases , Humans , Anti-Bacterial Agents/pharmacology , Antimicrobial Peptides , Antimicrobial Cationic Peptides/pharmacology , Antimicrobial Cationic Peptides/therapeutic use , Antimicrobial Cationic Peptides/chemistry , Anti-Infective Agents/therapeutic use , Anti-Infective Agents/chemistry , Communicable Diseases/drug therapyABSTRACT
Hybrid peptides from cecropin A and melittin have attracted the interest of the research community for decades. Here we synthesized several new analogs of the pentadecapeptide CA(1-7)M(2-9) and studied their antibacterial and hemolytic activity and tryptic stability. Single substitution of the Lys residues by Arg did not have a significant impact on the antibacterial activity of these analogs, but the substitution of the five Lys residues by Arg resulted in an increment in hemolytic activity. In contrast, the substitution of Lys residues by Orn conserved the antibacterial activity, with even lower hemolysis, and improved the enzymatic stability. The disulfide cyclic version of CA(1-7)M(2-9) was obtained by adding a Cys residue to each end of the peptide and carrying out a chemoselective thiol-disulfide interchange using sec-isoamylmecaptan as protecting group of one of these residues. This cyclic peptide showed good antibacterial activity with low hemolysis and improved enzymatic stability.
ABSTRACT
Oxazole-containing peptides are mostly of marine origin and they form an intriguing family with a broad range of biological activities. Here we classify these peptides on the basis of their chemical structure and discuss a number of representatives of each class that reflect the extraordinary potential of this family as a source of new drugs.
Subject(s)
Aquatic Organisms , Oxazoles/chemistry , Animals , Drugs, InvestigationalABSTRACT
Oxazole-containing peptides are an important class of molecules in medicinal chemistry programs. Here we describe a convenient solid-phase synthesis of Nα-terminal oxazole peptides. The strategy took advantage of an intramolecular rearrangement side reaction that occurred during the guanidination of the Nα-amino function of a peptide still anchored on the solid-support. The substitution map of the N,N-dialkylamino oxazole obtained using this strategy differed completely from the one achieved through the heterocyclization of the Ser or Thr side chain with the preceding carbonyl group, which is a common approach for the preparation of these compounds. This unexpected reaction was observed with N-terminal aromatic and aliphatic amino acids that have a Gly as the last before residue in both short as well as long peptides; however, it does not form the oxazole ring if Gly was substituted with other amino acids.
