Kadie Holsinger

Antibiotics (Basel). 2022 Dec 8;11(12):1772. doi: 10.3390/antibiotics11121772.

ABSTRACT

Cell-penetrating peptides (CPPs) are natural or engineered peptide sequences with the intrinsic ability to internalize into a diversity of cell types and simultaneously transport hydrophilic molecules and nanomaterials, of which the cellular uptake is often limited. In addition to this primordial activity of cell penetration without membrane disruption, multivalent antimicrobial activity accompanies some CPPs. Antimicrobial peptides (AMPs) with cell-penetrability exert their effect intracellularly, and they are of great interest. CPPs with antimicrobial activity (CPAPs) comprise a particular class of bioactive peptides that arise as promising agents against difficult-to-treat intracellular infections. This short review aims to present the antibacterial, antiparasitic, and antiviral effects of various cell-penetrating antimicrobial peptides currently documented. Examples include the antimicrobial effects of different CPAPs against bacteria that can propagate intracellularly, like Staphylococcus sp., Streptococcus sp., Chlamydia trachomatis, Escherichia coli, Mycobacterium sp., Listeria sp., Salmonella sp. among others. CPAPs with antiviral effects that interfere with the intracellular replication of HIV, hepatitis B, HPV, and herpes virus. Additionally, CPAPs with activity against protozoa of the genera Leishmania, Trypanosoma, and Plasmodium, the etiological agents of Leishmaniasis, Chagas' Disease, and Malaria, respectively. The information provided in this review emphasizes the potential of multivalent CPAPs, with anti-infective properties for application against various intracellular infections. So far, CPAPs bear a promise of druggability for the translational medical use of CPPs alone or in combination with chemotherapeutics. Moreover, CPAPs could be an exciting alternative for pharmaceutical design and treating intracellular infectious diseases.

PMID:36551429 | PMC:PMC9774436 | DOI:10.3390/antibiotics11121772

Curr Microbiol. 2022 Dec 17;80(1):38. doi: 10.1007/s00284-022-03150-7.

NO ABSTRACT

PMID:36527519 | DOI:10.1007/s00284-022-03150-7

J Am Chem Soc. 2022 Dec 18. doi: 10.1021/jacs.2c10949. Online ahead of print.

NO ABSTRACT

PMID:36530144 | DOI:10.1021/jacs.2c10949

Gut Microbes. 2023 Jan-Dec;15(1):2157698. doi: 10.1080/19490976.2022.2157698.

NO ABSTRACT

PMID:36524841 | DOI:10.1080/19490976.2022.2157698

Biophys J. 2022 Dec 14:S0006-3495(22)03927-3. doi: 10.1016/j.bpj.2022.12.017. Online ahead of print.

NO ABSTRACT

PMID:36523159 | DOI:10.1016/j.bpj.2022.12.017

FEBS Open Bio. 2022 Dec 15. doi: 10.1002/2211-5463.13537. Online ahead of print.

NO ABSTRACT

PMID:36520007 | DOI:10.1002/2211-5463.13537

J Agric Food Chem. 2022 Dec 13. doi: 10.1021/acs.jafc.2c05921. Online ahead of print.

NO ABSTRACT

PMID:36511360 | DOI:10.1021/acs.jafc.2c05921

Int J Mycobacteriol. 2022 Oct-Dec;11(4):343-348. doi: 10.4103/ijmy.ijmy_187_22.

NO ABSTRACT

PMID:36510916 | DOI:10.4103/ijmy.ijmy_187_22

Acta Biomater. 2022 Dec 9:S1742-7061(22)00783-8. doi: 10.1016/j.actbio.2022.11.055. Online ahead of print.

ABSTRACT

Infections induced by intracellular pathogens are difficult to eradicate due to poor penetration of antimicrobials into cell membranes. It is of great importance to develop a new generation of antibacterial agents with dual functions of efficient cell penetration and bacterial inhibition. In this study, the association between hydrophobicity and cell-penetrating peptide delivery efficiency was investigated by fragment interception and hydrophobicity modification of natural porcine antimicrobial peptide PR-39 and the combination of cationic cell-penetrating peptide (R6) with antimicrobial peptide fragments modified with hydrophobic residues. The chimeric peptides P3I7 and P3L7, obtained through biofunctional screening, exhibited potent broad-spectrum antibacterial activity and low cytotoxicity. Moreover, P3I7 and P3L7 can effectively penetrate cells to eliminate intracellular pathogens mainly through endocytosis. The membrane destruction mechanism makes the peptides fast sterilizers and less prone to developing drug resistance. Finally, their good biocompatibility and antibacterial infection effects were verified in mice and piglets. To conclude, the chimeric peptides P3I7 and P3L7 show great potential as affordable and effective antimicrobial agents and may serve as ideal candidates for the treatment of intracellular bacterial infections. STATEMENT OF SIGNIFICANCE: The low permeability of antibacterial drugs makes infections induced by intracellular bacteria extremely difficult to treat. To address this issue, we designed chimeric peptides with dual cell-penetrating and antibacterial functions. The active peptides P3I7 and P3L7, acquired through functional screening have strong broad-spectrum antibacterial activity and powerful bactericidal effects against intracellular Staphylococcus aureus. The membrane permeation mechanism of P3I7 and P3L7 against bacteria endows fast bactericidal activity with low drug resistance. The biosafety and antibacterial activity of P3I7 and P3L7 were also validated by in vivo trials. This study provides an ideal drug candidate against intracellular bacterial infections.

PMID:36503077 | DOI:10.1016/j.actbio.2022.11.055

Environ Microbiol. 2022 Dec 13. doi: 10.1111/1462-2920.16309. Online ahead of print.

NO ABSTRACT

PMID:36510854 | DOI:10.1111/1462-2920.16309

Molecules. 2022 Nov 24;27(23):8182. doi: 10.3390/molecules27238182.

ABSTRACT

Sortase A (SrtA) of Staphylococcus aureus is a well-defined molecular target to combat the virulence of these clinically important bacteria. However up to now no efficient drugs or even clinical candidates are known, hence the search for such drugs is still relevant and necessary. SrtA is a complex target, so many straight-forward techniques for modeling using the structure-based drug design (SBDD) fail to produce the results they used to bring for other, simpler, targets. In this work we conduct theoretical studies of the binding/activity of Leu-Pro-Arg-Asp-Ala (LPRDA) polypeptide, which was recently shown to possess antivirulence activity against S. aureus. Our investigation was aimed at establishing a framework for the estimation of the key interactions and subsequent modification of LPRDA, targeted at non-peptide molecules, with better drug-like properties than the original polypeptide. Firstly, the available PDB structures are critically analyzed and the criteria to evaluate the quality of the ligand-SrtA complex geometry are proposed. Secondly, the docking protocol was investigated to establish its applicability to the LPRDA-SrtA complex prediction. Thirdly, the molecular dynamics studies were carried out to refine the geometries and estimate the stability of the complexes, predicted by docking. The main finding is that the previously reported partially chaotic movement of the β6/β7 and β7/β8 loops of SrtA (being the intrinsically disordered parts related to the SrtA binding site) is exaggerated when SrtA is complexed with LPRDA, which in turn reveals all the signs of the flexible and structurally disordered molecule. As a result, a wealth of plausible LPRDA-SrtA complex conformations are hard to distinguish using simple modeling means, such as docking. The use of more elaborate modeling approaches may help to model the system reliably but at the cost of computational efficiency.

PMID:36500275 | PMC:PMC9890316 | DOI:10.3390/molecules27238182

Drugs. 2022 Dec;82(18):1695-1715. doi: 10.1007/s40265-022-01817-w. Epub 2022 Dec 7.

NO ABSTRACT

PMID:36479687 | PMC:PMC9734533 | DOI:10.1007/s40265-022-01817-w

Biochim Biophys Acta Mol Cell Res. 2022 Dec 5;1870(2):119406. doi: 10.1016/j.bbamcr.2022.119406. Online ahead of print.

NO ABSTRACT

PMID:36473551 | DOI:10.1016/j.bbamcr.2022.119406

J Agric Food Chem. 2022 Dec 21;70(50):15869-15878. doi: 10.1021/acs.jafc.2c06588. Epub 2022 Dec 5.

ABSTRACT

Antimicrobial peptides (AMPs) have broad-spectrum antibacterial properties and safety as food preservatives, whereas the stability and antibacterial activity require improvement. Here, the "head-to-tail" cyclization of linear AMP GKE was catalyzed by butelase 1, which resulted in an improved pronouncedly antibacterial effect. Cell morphology and propidium iodide uptake revealed that the increased membrane permeability was one of the bacteriostatic mechanisms of GKE and could be enhanced after cyclization. As cyclic GKE (cGKE) exhibited more stability than the linear counterpart under the microorganism culture environment, the increase in effective bacteriostatic concentration should be a reason for the superior antibacterial effect. Moreover, cGKE exhibited the ordered secondary structure, while GKE possessed a similar structure only in sodium dodecyl sulfate micelles. The structure was also beneficial to improve the antibacterial activity caused by the increased affinity of cGKE to the membranes. Overall, butelase 1-mediated cyclization is a promising strategy for enhancing the antibacterial activity of linear AMPs.

PMID:36471508 | DOI:10.1021/acs.jafc.2c06588

Indian J Microbiol. 2022 Dec;62(4):524-530. doi: 10.1007/s12088-022-01045-6. Epub 2022 Oct 28.

NO ABSTRACT

PMID:36458225 | PMC:PMC9705633 | DOI:10.1007/s12088-022-01045-6

J Enzyme Inhib Med Chem. 2023 Dec;38(1):387-397. doi: 10.1080/14756366.2022.2149745.

NO ABSTRACT

PMID:36446617 | PMC:PMC9718554 | DOI:10.1080/14756366.2022.2149745

J Med Chem. 2022 Nov 28. doi: 10.1021/acs.jmedchem.2c01469. Online ahead of print.

ABSTRACT

We designed a library of 24 cyclic peptides containing arginine (R) and tryptophan (W) residues in a sequential manner [R_nW_n] (n = 2-7) to study the impact of the hydrophilic/hydrophobic ratio, charge, and ring size on the antibacterial activity against Gram-positive and Gram-negative strains. Among peptides, 5a and 6a demonstrated the highest antimicrobial activity. In combination with 11 commercially available antibiotics, 5a and 6a showed remarkable synergism against a large panel of resistant pathogens. Hemolysis (HC₅₀ = 340 μg/mL) and cell viability against mammalian cells demonstrated the selective lethal action of 5a against bacteria over mammalian cells. Calcein dye leakage and scanning electron microscopy studies revealed the membranolytic effect of 5a. Moreover, the stability in human plasma (t_1/2 = 3 h) and the negligible ability of pathogens to develop resistance further reflect the potential of 5a for further development as a peptide-based antibiotic.

PMID:36442155 | DOI:10.1021/acs.jmedchem.2c01469

Antibiotics (Basel). 2022 Nov 13;11(11):1619. doi: 10.3390/antibiotics11111619.

ABSTRACT

Antimicrobial peptides (AMPs) can combat drug-resistant bacteria with their unique membrane-disruptive mechanisms. This study aimed to investigate the antibacterial effects of several membrane-acting peptides with amphipathic structures and positional alterations of two tryptophan residues. The synthetic peptides exhibited potent antibacterial activities in a length-dependent manner against various pathogenic drug-resistant and susceptible bacteria. In particular, the location of tryptophan near the N-terminus of AMPs simultaneously increases their antibacterial activity and toxicity. Furthermore, the growth inhibition mechanisms of these newly designed peptides involve cell penetration and destabilization of the cell membrane. These findings provide new insights into the design of peptides as antimicrobial agents and suggest that these peptides can be used as substitutes for conventional antibiotics.

PMID:36421263 | DOI:10.3390/antibiotics11111619