The activity and action mechanism of novel short selective LL‐37‐derived anticancer peptides against clinical isolates of Escherichia coli

Human cathelicidin LL‐37 has recently attracted interest as a potential therapeutic agent, mostly because of its ability to kill a wide variety of pathogens and cancer cells. In this study, we aimed to investigate the antibacterial activity and cytotoxicity of previously designed LL‐37 anticancer derivatives (i.e., P7, P22, and P38). Calcein release assay and field emission‐scanning electron microscopy (FE‐SEM) were performed to elucidate the possible mechanism of action of P38, the peptide with the highest bactericidal activity. In silico analysis demonstrated the amphipathic alpha‐helical structure for three peptides. Antibacterial activity of P38 against multidrug‐resistant (MDR) clinical isolates of Escherichia coli was higher than that of P7 and P22. P38 caused no hemolysis or cytotoxicity. Treating calcein‐loaded E. coli with 4× MIC of P38 resulted in more than 96% leakage of calcein. Noticeably, FE‐SEM revealed that P38 killed E. coli by disrupting the bacterial membrane. Molecular docking studies showed that P38 had a much higher affinity for the outer membrane of Gram‐negative bacteria compared with both P22 and P7. Owing to the bactericidal activity of P38 against MDR E. coli isolates and its negligible cytotoxicity, P38 has the potential for further studies in a mouse model of infectious disease.     

Cathelicidin peptide SMAP‐29: comprehensive review of its properties and potential as a novel class of antibiotics

Sheep myeloid antimicrobial peptide of 29 amino acids (SMAP‐29) is one of the most potent antimicrobial peptides known, with a broad spectrum of activity against bacteria, fungi, and viruses. It has also been shown to prevent infections in animals. SMAP‐29 is an α‐helical cathelicidin that acts rapidly to permeabilize membranes of susceptible organisms. However, it is also cytotoxic and hemolytic to mammalian cells. In this review, all published data on inhibition constants and hemolytic activities of SMAP‐29 are brought together for the first time, including data for the peptide of 28 residues that lacks the C‐terminal glycine and that also has the new C‐terminal residue amidated. Both peptides have been called SMAP‐29 in the literature. Antimicrobial activity of SMAP‐29 variants (including ovispirins) against Gram‐positive bacteria is also comprehensively tabulated, and anomalies in the nomenclature of the ovispirins are highlighted. The secondary structure, mode of action, and structure–activity relationships of SMAP‐29 are outlined, and the properties that indicate its therapeutic potential are identified; these are its broad‐spectrum antimicrobial activity with high potency, rapid biocidal action, limited development of bacterial resistance, synthesis by recombinant technology, ability to bind lipopolysaccharide, and demonstrated protection against infection in animal models. The limitations of SMAP‐29 are its high cytotoxicity and hemolytic activity, reduced activity under physiological conditions, and limited evidence for synergistic effects in combination with conventional antibiotics. Strategies with the potential to improve the selectivity toward pathogenic microorganisms over mammalian cells have been devised by the authors and are outlined. Drug Dev Res 70: 481–498, 2009. © 2009 Commonwealth of Australia; Published 2009 Wiley‐Liss, Inc.     

Interactions of the antimicrobial peptide Ac‐FRWWHR‐NH2 with model membrane systems and bacterial cells

Abstract: The acetylated and amidated hexapeptide FRWWHR (combi‐2), previously identified by combinatorial chemistry methods, shows strong antimicrobial activity. The binding of the peptide to 1‐palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐[(phospho‐rac‐(1‐glycerol)] (POPG) and 1‐palmitoyl‐2‐oleoyl‐sn‐glycero‐3‐phosphocholine (POPC) vesicles was studied using fluorescence spectroscopy and isothermal titration calorimetry (ITC). Differential scanning calorimetry (DSC) with dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) multilamellar vesicles was performed to determine changes in the lipid phase behaviour upon binding the peptide. Two‐dimensional proton nuclear magnetic resonance (NMR) spectroscopy, to solve the bound peptide structure, was performed in the presence of dodecylphosphatidylcholine (DPC) and sodium dodecyl sulphate (SDS) micelles. The fluorescence, ITC and DSC studies indicate that the peptide interacts preferentially with lipid vesicles containing negatively charged head groups. Conformational information determined using NMR indicate that the combi‐2 peptide adopts a coiled amphipathic conformation when bound to SDS and DPC micelles. Leakage assays indicate that the peptide is not very efficient at causing leakage from calcein‐filled large unilamellar vesicles comprised of POPG/POPC (1 : 1). The rapid passage of either the fluorescent‐tagged peptides combi‐2 or the previously studied peptide Ac‐RRWWRF‐NH₂ (combi‐1) into Escherichia coli and Staphylococcus aureus suggests that instead of membrane disruption, the main bactericidal site of action of these peptides might be located inside bacteria.     

Antibacterial,antitumor and hemolytic activities of α‐helical antibiotic peptide,P18 and its analogs

Abstract: The α‐helical antibiotic peptide (P18: KWKLFKKIPKFLHLAKKF‐NH₂) designed from the cecropin A(1–8)–magainin 2 (1?12) hybrid displayed strong bactericidal and tumoricidal activity without inducing hemolysis. The effect of the Pro⁹ residue at central position of P18 on cell selectivity was investigated by Pro⁹ → Leu or Pro⁹ → Ser substitution. Either substitution markedly reduced the antibacterial activity of P18 and increased hemolysis, although it did not significantly affect cytotoxicity against human transformed tumor and normal fibroblast cells. These results suggest that a proline kink in α‐helical antibiotic peptide P18 serves as a hinge region to facilitate ion channel formation on bacterial cell membranes and thus plays an important role in providing high selectivity against bacterial cells. Furthermore, to investigate the structure?antibiotic activity relationships of P18, a series of N‐ or C‐terminal deletion and substitution analogs of P18 were synthesized. The C‐terminal region of P18 was related to its antibiotic activity and α‐helical conformation on lipid membranes rather than N‐terminal one. Higher α‐helicity of the peptides was involved in the hemolytic and antitumor activity rather than antibacterial activity. Except for [L⁹]‐P18 and [S⁹]‐P18, all the designed peptides containing a Pro residue showed potent antibacterial activity, although they did not induce a cytolytic effect against human erythrocyte and normal fibroblast cells at the concentration required to kill bacteria. In particular, P18 and some analogs (N‐1, N‐2, N‐3, N‐3L and N‐4L) with potent bactericidal and tumoricidal activity and little or no normal cell toxicity may serve as an attractive candidate for the development of novel anti‐infective or antitumor agents.     

In Vitro and In Vivo Evaluation of Small Cationic Abiotic Lipopeptides as Novel Antifungal Agents

We investigated the antifungal potential of short lipopeptides against clinical fungal isolates with an objective to evaluate their clinical feasibility. All tested lipopeptides exhibit good antifungal activity with negligible difference between the MICs against susceptible and drug‐resistant clinical fungal isolates. The MTT assay results revealed the lower cytotoxicity of lipopeptides toward mammalian cells (NRK‐52E). In particular, LP24 displayed highest potency against most of the tested fungal isolates with MICs in the range of 1.5–4.5 μg/mL. Calcein dye leakage experiments with model membrane suggested the membrane‐active mode of action for LP24. Extending our work from model membranes to intact Aspergillus fumigatus in scanning electron micrographs, we could visualize surface perturbation caused by LP24. LP24 (5 mg/kg) significantly reduces the A. fumigatus burden among the various organs of infected animals, and 70% of the infected mice survived when observed for 28 days. This study underscores the potential of small cationic abiotic lipopeptides to develop into the next‐generation antimicrobial therapy.     

Production of an Antimicrobial Peptide AN5‐1 in Escherichia coli and its Dual Mechanisms Against Bacteria

AN5‐1 (YSKSLPLSVLNP) is an antimicrobial peptide isolated from the fermentation broth of Paenibacillus alvei strain AN5 (J Ind Microb Biotechnol 2013; 40 : 571–9). In this study, we report the application of ubiquitin fusion technology to the expression and purification of AN5‐1. Minimum inhibitory concentration (MIC) and measurement of hemolytic activity (MHC) were measured to confirm the biological activities of the expressed AN5‐1. Bacterial cell membrane permeabilization was investigated to show the interaction between the AN5‐1 and the bacterial cytoplasmic membrane. Furthermore, intracellular activities of the AN5‐1 were determined by genomic DNA interaction assays. The results revealed AN5‐1 damaging bacterial membranes and binding to bacterial genomic DNA to inhibit cellular functions, suggesting that it has multiple intracellular targets in bacteria. The application of ubiquitin fusion technology may be an excellent approach for industrial production to the expression and purification of antimicrobial peptide. Furthermore, AN5‐1 was demonstrated as an antimicrobial peptide with great potentials, as bacterial resistance to AN5‐1 would be not expected, due to the dual mechanisms of AN5‐1 against bacteria.     

Interaction of pleurocidin and its analogs with phospholipid membrane and their antibacterial activity

Abstract: A 25‐mer cationic peptide pleurocidin, isolated from the winter flounder, has broad antibacterial activity. To clarify the structure–activity relationship, its properties and biological activity were examined. CD measurements showed that pleurocidin took an α‐helical structure in the presence of DOPC/DOPG (3 : 1, anionic) vesicles. Very weak hemolytic activity of pleurocidin was observed and its antibacterial activity was moderate. Tryptophan fluorescence shift measurements showed that pleurocidin interacted weakly with a neutral phospholipid, but strongly with an acidic phospholipid. The peptide exhibited weak dye‐leakage activity for DOPC (neutral) vesicles and moderate activity for acidic vesicles. From experiments on dye‐leakage activity and membrane translocation of the peptide, it seemed likely that pleurocidin, like magainin 2, forms pores in the lipid membrane. A study of amino acid substitution in pleurocidin revealed that α‐helicity, rather than hydrophobicity, affects the properties and activity of the peptide.     

Preliminary investigations into developing all‐D Omiganan for treating Mupirocin‐resistant MRSA skin infections

Staphylococcus aureus is the primary pathogen responsible for the majority of human skin infections, and meticillin‐resistant S. aureus (MRSA) currently presents a major clinical concern. The overuse of Mupirocin, the first‐line topical antibacterial drug over 30 years, has led to the emergence of Mupirocin‐resistant MRSA, creating a clinical concern. The antimicrobial peptide Omiganan was touted to be a promising antibacterial drug candidate due to its rapid membrane‐disrupting bactericidal mode of action, entering clinical trials in 2005 as a topical gel to prevent catheter site infections. However, drug development ceased in 2009 due to a lack of efficacy. We postulate this to be due to proteolytic degradation caused by endogenous human skin proteases. Herein, we tested our hypothesis using Omiganan and its all‐D enantiomer in a human skin protease stability assay, followed by anti‐MRSA activity assay against of a panel of clinical MRSA isolates, a bactericidal/static determination and a time‐kill assay to gauge all‐D Omiganan's potential for further topical antibacterial drug development.     

Syntheses and structure–membrane active antimicrobial activity relationship of alkylamino‐modified glucose,maltooligosaccharide, and amylose

Antimicrobial alkylamine‐modified sugars were prepared. Microwave‐assisted click reaction efficiently achieved poly‐functionalization of oligo‐ and polysaccharides. The sugars exhibited a unique relationship of their bacterial membrane permeabilization and antimicrobial activity with the number of functional groups and the structure of the molecular scaffold. It shows that the assembly of the functional groups is necessary for being antimicrobial. The amylose derivatives also exhibited synergy to minimize the necessary dose of conventional antibiotics and increase their antimicrobial potency.     

Insulinotropic Actions of the Frog Skin Host‐Defense Peptide Alyteserin‐2a: A Structure–Activity Study

Alyteserin‐2a (ILGKLLSTAAGLLSNL.NH₂) stimulated the rate of insulin release from BRIN‐BD11 clonalβ cells at a concentration of 30 nm (p < 0.05) with a response of 296 ± 26% of basal release at 3 μm (p < 0.001). The insulinotropic actions of analogs containing substitutions by l ‐lysine, d ‐lysine, or l ‐tryptophan at sites that maintain amphipathicity were evaluated. The [G11K], [S7k], [S7k,G11k], and [G11k,N15K] analogs were the most potent stimulating insulin release at 0.01 nm (p < 0.05). The [S7K], [G11K], [S14K], [N15K], [G11k], and [S7K,G11K] analogs were the most effective producing an approximately twofold greater (p < 0.001) release of insulin at 3 μm compared with alyteserin‐2a. The [T8W] and [A9W] analogs were less active than alyteserin‐2a. No peptide‐stimulated release of lactate dehydrogenase at concentrations up to 3 μm , indicating that the integrity of the plasma membrane had been preserved. Membrane depolarization and an increase in intracellular Ca²⁺ concentration are involved in the mechanism of action of the peptides. Administration of [G11k]alyteserin‐2a (75 nmol/kg body weight) to high‐fat‐fed mice with obesity and insulin resistance significantly (p < 0.01) enhanced insulin release and improved glucose tolerance during the 60‐min period following an intraperitoneal glucose load.     

Antimicrobial and antibiofilm activity of LL-37 and its truncated variants against Burkholderia pseudomallei

The Gram-negative bacterium Burkholderia pseudomallei is the aetiological agent of melioidosis, which is an endemic disease in tropical areas of Southeast Asia and Northern Australia. Burkholderia pseudomallei has intrinsic resistance to a number of commonly used antibiotics and has also been reported to develop a biofilm. Resistance to killing by antimicrobial agents is one of the hallmarks of bacteria grown in biofilm. The aim of this study was to determine the antimicrobial activity and mechanisms of action of LL-37 and its truncated variants against B. pseudomallei both in planktonic and biofilm form, as LL-37 is an antimicrobial peptide that possessed strong killing activity against several pathogens. Antimicrobial assays revealed that LL-31, a truncated variant of LL-37 lacking the six C-terminus residues, exhibited the strongest killing effect. Time-kill experiments showed that 20 μM LL-31 can reach the bactericidal endpoint within 2 h. Freeze-fracture electron microscopy of bacterial cells demonstrated that these peptides disrupt the membrane and cause leakage of intracellular molecules leading to cell death. Moreover, LL-31 also possessed stronger bactericidal activity than ceftazidime against B. pseudomallei grown in biofilm. Thus, LL-31 should be considered as a potent antimicrobial agent against B. pseudomallei both in planktonic and biofilm form.     

Antimicrobial activity of myotoxic phospholipases A2 from crotalid snake venoms and synthetic peptide variants derived from their C-terminal region.

A short peptide derived from the C-terminal region of Bothrops asper myotoxin II, a Lys49 phospholipase A(2) (PLA(2)), was previously found to reproduce the bactericidal activity of its parent molecule. In this study, a panel of eight PLA(2) myotoxins purified from crotalid snake venoms, including both Lys49 and Asp49-type isoforms, were all found to express bactericidal activity, indicating that this may be a common action of the group IIA PLA(2) protein family. A series of 10 synthetic peptide variants, based on the original C-terminal sequence 115-129 of myotoxin II and its triple Tyr-->Trp substituted peptide p115-W3, were characterized. In vitro assays for bactericidal, cytolytic and anti-endotoxic activities of these peptides suggest a general correlation between the number of tryptophan substitutions introduced and microbicidal potency, both against Gram-negative (Salmonella typhimurium) and Gram-positive (Staphylococcus aureus) bacteria. Peptide variants with high bactericidal activity also tended to be more cytolytic towards skeletal muscle C2C12 myoblasts, thus limiting their potential in vivo use. However, the peptide variant pEM-2 (KKWRWWLKALAKK) showed reduced toxicity towards muscle cells, while retaining high bactericidal potency. This peptide also showed the highest endotoxin-neutralizing activity in vitro, and was shown to functionally interact with lipopolysaccharide (LPS) using a chimeric bacteria model. The bactericidal and anti-endotoxic properties of pEM-2, combined with its relatively low toxicity towards eukaryotic cells, highlight it as a promising candidate for further evaluation of its antimicrobial potential in vivo.     

Design,synthesis, and antimicrobial activities of novel functional peptides against Gram‐positive and Gram‐negative bacteria

The extensive use of antibiotics in medicine results in the multidrug resistance of bacteria, making the development of new antimicrobial agents an urgent need. Antimicrobial peptides (AMPs) are considered as a new class of antibiotic with characteristics including an ability to kill target cells rapidly and a broad spectrum of activity. We have developed a potent antimicrobial peptide MAP‐0403 (MIC = 5 μM), but it exhibited a high hemolytic side‐effect (70.7%). To reduce its hemolytic effect and increase antimicrobial activity, three peptides derivatives of MAP‐0403 (J‐1, J‐2, and J‐3) were designed, synthesized by solid phase synthesis, purified by RP‐HPLC, and characterized by MALDI‐TOF MS. Structure–activity relationships of these peptides were studied by using circular dichroism and antimicrobial assays. The percentage of helical structure in J‐1, J‐2, and J‐3 was lower than that of MAP‐0403. The antimicrobial activity of J‐1 was the same as that of MAP‐0403 (MIC = 5 μM), J‐2 exhibited the highest activity (MIC = 2.5 μM), while J‐3 showed decreased activity (MIC = 10 μM). Compared to MAP‐0403, J‐2 showed significantly reduced hemolytic effect (3.4%), while J‐1 and J‐3 showed slightly decreased hemolytic effect (46.2%, 55.6%, respectively). Peptide J‐2 was discovered as a novel and potent antimicrobial agents.     

Effect of terminal arrangement of tryptophan on biological activity of symmetric α‐helix‐forming peptides

It is traditionally believed that the distribution of tryptophan (Trp) residues is critical for the novo design of antimicrobial peptides (AMPs). However, there is scarce knowledge regarding Trp residues arrangement at the head group level. Thus, a set of α‐helical AMPs containing different Trp residue arrangements at the N‐/C‐terminal of sequence were designed to increase the strategy database and analyze their biological activities. The arrangement of the N‐terminal Trp residue significantly improved the bacteriostatic activity of the peptides, but the C‐terminal Trp residue arrangement reduced the biocompatibility of them. WL and LW were effective against Gram‐negative microbes and had high selectivity for bacteria as compared to human erythrocytes and mammalian cells. They both maintained a relatively desirable activity in the presence of physiological salts and serum. It is observed through electron microscope, flow cytometry and fluorescence spectroscopy that target peptides can penetrate bacterial cell membrane and kill it by damaging cell membrane integrity. Collectively, we determined the structure–activity relationship of Trp residue distributions in a symmetric sequence structure and filled the gap in knowledge related to Trp arrangements at the head group level. The obtained results will be helpful in designing of artificial peptide‐based antimicrobials.     

Effect of FSH Receptor‐Binding Inhibitor‐8 on FSH‐Mediated Granulosa Cell Signaling and Proliferation

Follicle‐stimulating hormone is important for mammalian reproduction. It acts through specific receptors located on the plasma membrane of granulosa cells in ovaries and Sertoli cells in testes. The binding of follicle‐stimulating hormone to its receptor activates intracytoplasmic signaling pathways leading to steroidogenesis. These steroids in turn regulate the follicle‐stimulating hormone action from the anterior pituitary through exerting negative feedback effect. In addition to steroids, non‐steroidal factors secreted by the ovaries are believed to modulate follicle‐stimulating hormone action through autocrine/paracrine mode. One such low molecular weight peptide referred to as follicle‐stimulating hormone receptor‐binding inhibitor‐8 purified from human follicular fluid has been extensively studied. Follicle‐stimulating hormone receptor‐binding inhibitor‐8 has been shown to inhibit binding of follicle‐stimulating hormone to its receptor. The present article describes the effect of follicle‐stimulating hormone receptor‐binding inhibitor‐8 on follicle‐stimulating hormone‐induced signaling in rat granulosa cells. Follicle‐stimulating hormone receptor‐binding inhibitor‐8 inhibited the follicle‐stimulating hormone‐induced cAMP, and the effect was observed to be mediated through the protein kinase A. Further, an inhibitory effect of follicle‐stimulating hormone receptor‐binding inhibitor‐8 on the granulosa cell proliferation was evaluated using COV434 cell line which is derived from the human granulosa cell tumor. The effect of the peptide on the cell cycle analysis showed an increase in apoptotic population and the arrest of G1 phase. These findings suggest that follicle‐stimulating hormone receptor‐binding inhibitor‐8 acts as a follicle‐stimulating hormone antagonist and affects the follicle‐stimulating hormone‐mediated signaling and proliferation in the granulosa cells.     

Solid‐phase synthesis of polymyxin B1 and analogues via a safety‐catch approach

Abstract: As part of a program towards the development of novel antibiotics, a convenient method for solid‐phase synthesis of the cyclic cationic peptide polymyxin B1 and analogues thereof is described. The methodology, based on cleavage‐by‐cyclization using Kenner's safety‐catch linker, yields crude products with purities ranging from 37–67%. Antibacterial assays revealed that analogues 23–26 , in which the (S)‐6‐methyloctanoic acid moiety is replaced with shorter acyl chains, exhibit distinct antimicrobial activity. The results suggest that the length of the acyl chain is rather critical for antimicrobial activity. On the other hand, substitution of the hydrophobic ring‐segment D‐Phe‐6/Leu‐7 in polymyxin B1 with dipeptide mimics (i.e. analogues 27–33 ) resulted in almost complete loss of antimicrobial activity.     

Synthesis and Biological Evaluation of 2‐Mercapto‐1,3‐benzothiazole Derivatives with Potential Antimicrobial Activity

The enhancement of bacterial resistance of pathogens to currently available antibiotics constitutes a serious public health threat. So, intensive efforts are underway worldwide to develop new antimicrobial agents. To identify compounds with a potent antimicrobial profile, we designed and synthesized low molecular weight 2‐mercaptobenzothiazole derivatives 2a – 2l and 3a – 3l . Both series were screened for in‐vitro antibacterial activity against the representative panel of Gram‐positive and Gram‐negative bacteria strains. The biological screening identified compounds 2e and 2l as the most active ones showing an interesting antibacterial activity with MIC values of 3.12 μg/mL against Staphylococcus aureus and 25 μg/mL against Escherichia coli, respectively. The replacement of the S‐H by the S‐Bn moiety resulted in considerable loss of the antibacterial action of the 3a – 3l series. The antibiotic action of compounds 2e and 2l was also investigated by testing their activity against some clinical isolates with different antimicrobial resistance profile. Moreover, the involvement of the NorA efflux pump in the antibacterial activity of our molecules was evaluated. Finally, in this paper, we also describe the cytotoxic activity of the most interesting compounds by MTS assay against HeLa and MRC‐5 cell lines.     

Design of a pH‐sensitive pore‐forming peptide with improved performance

Abstract: GALA is a 30 residue synthetic peptide designed to interact with membranes in a pH‐sensitive manner, with potential applications for intracellular drug and gene delivery. Upon reduction of the pH from neutral to acidic, GALA switches from random coil to α‐helix, inserts into lipid bilayers, and forms oligomeric pores of defined size. Its simple sequence and well‐characterized behavior make the peptide an excellent starting point to explore the effects of sequence on structure, pH sensitivity, and membrane affinity. We describe synthesis and characterization of two derivatives of GALA, termed GALAdel3E and YALA. GALAdel3E has a deletion of three centrally located glutamate residues from GALA, while YALA replaces one glutamate residue with the unusual amino acid 3,5‐diiodotyrosine. Both derived peptides retain pH sensitivity, showing no ability to cause leakage of an encapsulated dye from unilamellar vesicles at pH 7.4 but substantial activity at pH 5. Unlike GALA, neither peptide undergoes a conformational change upon reduction of the pH, remaining α‐helical throughout. Interestingly, the pH at which the peptides activate is shifted, with GALA becoming active at pH ～5.7, GALAdel3E at pH ～6.2, and YALA at pH ～6.7. Furthermore, the peptides GALAdel3E and YALA show improved activity compared with GALA for cholesterol‐containing membranes, with YALA retaining the greatest activity. Improved activity in the presence of cholesterol and onset of activity in the critical range between pH 6 and 7 may make these peptides useful in applications requiring intracellular delivery of macromolecules, such as gene delivery or anti‐cancer treatments.     

Synthesis and biological evaluation of novel peptides based on antimicrobial peptides as potential agents with antitumor and multidrug resistance‐reversing activities

Tumor chemotherapy, which plays an important role in the clinical treatment of metastatic cancer, is limited by low selectivity and drug resistance in clinical application. In our study, we selected antimicrobial peptide BP100 as a lead peptide, designed, and synthesized a series of novel antineoplastic peptides through solid‐phase synthesis. Among them, B4 and B8 showed excellent anticancer activity. As revealed by further investigations, these peptides could disrupt the cell membrane, trigger the cytochrome C release into cytoplasm, and ultimately lead to apoptosis. In addition, they also showed multidrug resistance‐reversing effects by performing effective antitumor activity against multidrug‐resistant cells. As a result, these peptides may possibly be regarded as a promising candidate for cancer treatment.