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Antibacterial Activity of Rationally Designed Antimicrobial Peptides.

ABSTRACT: Many infectious diseases are still prevalent in the world's populations since no effective treatments are available to eradicate them. The reasons may either be the antibiotic resistance towards the available therapeutic molecules or the slow rate of producing adequate therapeutic regimens to tackle the rapid growth of new infectious diseases, as well as the toxicity of current treatment regimens. Due to these reasons, there is a need to seek and develop novel therapeutic regimens to reduce the rapid scale of bacterial infections. Antimicrobial Peptides (AMPs) are components of the first line of defense for prokaryotes and eukaryotes and have a wide range of activities against Gram-negative and Gram-positive bacteria, fungi, cancer cells, and protozoa, as well as viruses. In this study, peptides which were initially identified for their HIV inhibitory activity were further screened for antibacterial activity through determination of their kinetics as well as their cytotoxicity. From the results obtained, the MICs of two AMPs (Molecule 3 and Molecule 7) were 12.5??g/ml for K. pneumoniae (ATCC 700603) and 6.25??g/ml for P. aeruginosa (ATCC 22108). The two AMPs killed these bacteria rapidly in vitro, preventing bacterial growth within few hours of treatment. Furthermore, the cytotoxic activity of these two peptides was significantly low, even at an AMP concentration of 100??g/ml. These results revealed that Molecule 3 and 7 have great potential as antibacterial drugs or could serve as lead compounds in the design of therapeutic regimens for the treatment of antibiotic-resistant bacteria.

SUBMITTER: Tincho MB

PROVIDER: S-EPMC7168710 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Antibacterial Activity of Rationally Designed Antimicrobial Peptides.

Tincho Marius B MB Morris Thureyah T Meyer Mervin M Pretorius Ashley A

International journal of microbiology 20200408

Many infectious diseases are still prevalent in the world's populations since no effective treatments are available to eradicate them. The reasons may either be the antibiotic resistance towards the available therapeutic molecules or the slow rate of producing adequate therapeutic regimens to tackle the rapid growth of new infectious diseases, as well as the toxicity of current treatment regimens. Due to these reasons, there is a need to seek and develop novel therapeutic regimens to reduce the ...[more]

PMID: 32322274

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Project description:Combating the spread of antimicrobial resistance (AMR) among bacteria requires a new class of antimicrobials, which desirably have a narrow spectrum because of their low propensity for the spread of AMR. Antimicrobial peptides (AMPs), which target the bacterial cell membrane, are promising seeds for novel antimicrobials because the cell membrane is essential for all cells. Previously, we reported the antimicrobial and haemolytic effects of a natural AMP, magainin 2 (Mag2), isolated from the skin of Xenopus laevis (the African clawed frog), four types of synthesised Mag2 derivatives, and three types of rationally designed AMPs on gram-positive and gram-negative bacteria. To identify novel antimicrobial seeds, we evaluated the effect of AMPs on Mycoplasma pneumoniae, which also exhibits AMR. We also evaluated the antimicrobial effects of an AMP, NK2A, which has been reported to have antimicrobial effects on Mycoplasma bovis, in addition to Mag2 and previously synthesised seven AMPs, on four strains of M. pneumoniae using colorimetric, biofilm, and killing assays. We found that three synthesised AMPs, namely 17base-Ac6c, 17base-Hybrid, and Block, had anti-M. pneumoniae (anti-Mp) effect at 8-30 μM, whereas others, including NK2A, did not have any such effect. For the further analysis, the membrane disruption activities of AMPs were measured by propidium iodide (PI) uptake assays, which suggested the direct interaction of AMPs to the cell membrane basically following the colorimetric, biofilm, and killing assay results. PI uptake assay, however, also showed the NK2A strong interaction to cell membrane, indicating unknown anti-Mp determinant factors related to the peptide sequences. Finally, we conclude that anti-Mp effect was not simply determined by the membrane disruption activities of AMPs, but also that the sequence of AMPs were important for killing of M. pneumoniae. These findings would be helpful for the development of AMPs for M. pneumoniae.

Project description:Virus capsid assembly constitutes an attractive target for the development of antiviral therapies; a few experimental inhibitors of this process for HIV-1 and other viruses have been identified by screening compounds or by selection from chemical libraries. As a different, novel approach we have undertaken the rational design of peptides that could act as competitive assembly inhibitors by mimicking capsid structural elements involved in intersubunit interfaces. Several discrete interfaces involved in formation of the mature HIV-1 capsid through polymerization of the capsid protein CA were targeted. We had previously designed a peptide, CAC1, that represents CA helix 9 (a major part of the dimerization interface) and binds the CA C-terminal domain in solution. Here we have mapped the binding site of CAC1, and shown that it substantially overlaps with the CA dimerization interface. We have also rationally modified CAC1 to increase its solubility and CA-binding affinity, and designed four additional peptides that represent CA helical segments involved in other CA interfaces. We found that peptides CAC1, its derivative CAC1M, and H8 (representing CA helix 8) were able to efficiently inhibit the in vitro assembly of the mature HIV-1 capsid. Cocktails of several peptides, including CAC1 or CAC1M plus H8 or CAI (a previously discovered inhibitor of CA polymerization), or CAC1M+H8+CAI, also abolished capsid assembly, even when every peptide was used at lower, sub-inhibitory doses. To provide a preliminary proof that these designed capsid assembly inhibitors could eventually serve as lead compounds for development of anti-HIV-1 agents, they were transported into cultured cells using a cell-penetrating peptide, and tested for antiviral activity. Peptide cocktails that drastically inhibited capsid assembly in vitro were also able to efficiently inhibit HIV-1 infection ex vivo. This study validates a novel, entirely rational approach for the design of capsid assembly interfacial inhibitors that show antiviral activity.

Dataset Information

Antibacterial Activity of Rationally Designed Antimicrobial Peptides.

Publications

Antibacterial Activity of Rationally Designed Antimicrobial Peptides.

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