SMAP-29 has two LPS-binding sites and a central hinge.

The CD spectra of SMAP-29, an antimicrobial peptide from sheep, showed disordered structure in aqueous buffers, and significant helicity in membrane-like environments, including SDS micelles, lipopolysaccharide (LPS) dispersions, and trifluoroethanol buffer systems. A structure determined by NMR in 40% perdeuterated trifluoroethanol indicated that residues 8-17 were helical, residues 18-19 formed a hinge, and residues 20-28 formed an ordered, hydrophobic segment. SMAP-29 was flexible in 40% trifluoroethanol, forming two sets of conformers that differed in the relative orientation of the N-terminal domain. We used a chromogenic Limulus assay to determine the EC50 of the peptide (the concentration that bound 50% of the added LPS). Studies with full-length and truncated SMAP-29 molecules revealed that each end of the holopeptide contained an LPS-binding domain. The higher affinity LPS-binding domain was situated in the flexible N-terminal portion. LPS binding to full-length SMAP-29 showed positive cooperativity, so the EC50 of the peptide (2.6 microm) was considerably lower than that of the individual LPS-binding domains. LPS-binding studies with a mixture of truncated peptides revealed that this cooperativity was primarily intramolecular (i.e. involving the N- and C-terminal LPS-binding sites of the same peptide molecule). CAP-18[106 -142], an antimicrobial cathelicidin peptide of rabbits, resembled SMAP-29 in that it contained N- and C-terminal LPS-binding domains, had an EC50 of 2.5 microm, and bound LPS with positive cooperativity. We conclude that the presence of multiple binding sites that function cooperatively allow peptides such as SMAP-29 and CAP-18 to bind LPS with high affinity.     

Bacterial killing mechanism of sheep myeloid antimicrobial peptide-18 (SMAP-18) and its Trp-substituted analog with improved cell selectivity and reduced mammalian cell toxicity

To develop short antimicrobial peptide with improved cell selectivity and reduced mammalian cell toxicity compared to sheep myeloid antimicrobial peptide-29 (SMAP-29) and elucidate the possible mechanisms responsible for their antimicrobial action, we synthesized a N-terminal 18-residue peptide amide (SMAP-18) from SMAP-29 and its Trp-substituted analog (SMAP-18-W). Due to their reduced hemolytic activity and retained antimicrobial activity, SMAP-18 and SMAP-18-W showed higher cell selectivity than SMAP-29. In addition, SMAP-18 and SMAP-18-W had no cytotoxicity against three different mammalian cells such as RAW 264.7, NIH-3T3 and HeLa cells even at 100 μM. These results suggest that SMAP-18 and SMAP-18-W have potential for future development as novel therapeutic antimicrobial agent. Unlike SMAP-29, SMAP-18 and SMAP-18-W showed relatively weak ability to induce dye leakage from bacterial membrane-mimicking liposomes, N-phenyl-1-napthylamine (NPN) uptake and o-nitrophenyl-β-galactoside (ONPG) hydrolysis. Similar to SMAP-29, SMAP-18-W led to a significant membrane depolarization (>80 %) against Staphylococcus aureus at 2 × MIC. In contrast, SMAP-18 did not cause any membrane depolarization even at 4 × MIC. In confocal laser scanning microscopy, we observed translocation of SMAP-18 across the membrane in a non-membrane disruptive manner. SMAP-29 and SMAP-18-W were unable to translocate the bacterial membrane. Collectively, we propose here that SMAP-29 and SMAP-18-W kill microorganisms by disrupting/perturbing the lipid bilayer and forming pore/ion channels on bacterial cell membranes, respectively. In contrast, SMAP-18 may kill bacteria via intracellular-targeting mechanism.     

SMAP-29: a potent antibacterial and antifungal peptide from sheep leukocytes

SMAP-29 is a cathelicidin-derived peptide deduced from sheep myeloid mRNA. The C-terminally amidated form of this peptide was chemically synthesized and shown to exert a potent antimicrobial activity. Antibiotic-resistant clinical isolates highly susceptible to this peptide include MRSA and VREF isolates, that are a major worldwide problem, and mucoid Pseudomonas aeruginosa associated with chronic respiratory inflammation in CF patients. In addition, SMAP-29 is also active against fungi, including Cryptococcus neoformans isolated from immunocompromised patients. SMAP-29 causes significant morphological alterations of the bacterial surfaces, as shown by scanning electron microscopy, and is also hemolytic against human, but not sheep erythrocytes. Its potent antimicrobial activity suggests that this peptide is an excellent candidate as a lead compound for the development of novel antiinfective agents.     

The molecular design of a recombinant antimicrobial peptide CP and its in vitro activity

Antibacterial peptides from various sources express different antibacterial activity. In order to obtain a high activity antibacterial peptide, the sequences of four antimicrobial peptides--Protegrin-1, 4 kDa Scorpion Defensin, Metalnikowin-2A and Sheep Myeloid Antibacterial Peptide SMAP-29--were exploited to generate a synthetic antimicrobial peptide cp gene, which was then cloned into the expression vector pPICZalpha-A. The constructed recombinant expression vector pPICZalpha-cp was transformed into Pichia pastoris X-33, in which the synthetic antimicrobial peptide (CP) could be expressed under the control of the inducible AOX1 promoter and secreted via the alpha mating factor leader of Saccharomyces cerevisiae. Results showed that recombinant plasmid is highly stable, and In vitro experiments showed that the recombinant antimicrobial peptide CP is heat and acid-stable, and it has high antibacterial activity against several Gram-positive and -negative bacteria. Only 1 microg of the recombinant antimicrobial peptide CP has an antibacterial activity equivalent to 64 U ampicillin. Thus, this recombinant antimicrobial peptide could serve as an attractive candidate for the development of therapeutic antimicrobial drugs.     

抗菌肽SMAP-29结构功能及分子设计策略

抗菌肽是生物体内产生的一种具有生物活性的小分子多肽,具有广谱抗细菌、抗病毒、抗真菌甚至抗癌作用。SMAP-29是来源于绵羊骨髓细胞,包含29个氨基酸的Cathelicidin类α-螺旋结构抗菌肽。SMAP-29具有多种生物活性,包括抗革兰氏阳/阴性菌、抗真菌、抗病毒、抗寄生虫、抗螺旋体、抗衣原体和中和内毒素活性,并且具有作用机制独特、快速杀灭细菌的特点。以下综述了SMAP-29抗菌肽家族的基因和蛋白结构、结构与活性关系、作用机制、生物功能、基因重组表达,重点阐述了SMAP-29结构、分子设计的必要性和基于     

Antifungal mechanism of SMAP-29 (1-18) isolated from sheep myeloid mRNA against Trichosporon beigelii

The antifungal activity and mechanism of SMAP-29 (1-18) (SMAP-29), a cathelicidin-derived antimicrobial peptide deduced from N-terminal sequence of sheep myeloid mRNA, were investigated. SMAP-29 displayed a strong antifungal activity against various fungi. To understand the antifungal mechanism(s) of SMAP-29, we examined the interaction of SMAP-29 with the pathogenic fungus Trichosporon beigelii. Confocal microscopy showed that SMAP-29 was localized in the plasma membrane. The antifungal effects of SMAP-29 were further confirmed by using 1,6-diphenyl-1,3,5-hexatriene (DPH) as a plasma membrane probe. Flow cytometric analysis revealed that SMAP-29 acted in an energy-dependent manner. This interaction is also dependent on the ionic environment. Furthermore, SMAP-29 caused significant morphological changes when testing the membrane disrupting activity using liposomes (phosphatidylcholine/cholesterol; 10:1, w/w), as shown by scanning electron microscopy. The results suggest that SMAP-29 may exert its antifungal activity by disrupting the structure of cell membranes, via direct interaction with the lipid bilayers and irregularly disrupted fungal membranes in an energy- and salt-dependent manner.     

Structure-activity relations of parasin I, a histone H2A-derived antimicrobial peptide

The structure-activity relations and mechanism of action of parasin I, a 19-amino acid histone H2A-derived antimicrobial peptide, were investigated. Parasin I formed an amphipathic alpha-helical structure (residues 9-17) flanked by two random coil regions (residues 1-8 and 18-19) in helix-promoting environments. Deletion of the lysine residue at the N-terminal [Pa(2-19)] resulted in loss of antimicrobial activity, but did not affect the alpha-helical content of the peptide. The antimicrobial activity was recovered when the lysine residue was substituted with another basic residue, arginine ([R(1)]Pa), but not with polar, neutral, or acidic residues. Progressive deletions from the C-terminal [Pa(1-17), Pa(1-15)] slightly increased the antimicrobial activity (1-4 microg/ml) without affecting the alpha-helical content of the peptide. However, further deletion [Pa(1-14)] resulted in nearly complete loss of antimicrobial activity and alpha-helical structure. Confocal microscopic analysis and membrane permeabilization assays showed that parasin I and its analogs with comparable antimicrobial activities localized to the cell membrane and subsequently permeabilized the outer and cytoplasmic membranes. Pa(1-14) also localized to the cell membrane, but lost membrane-permeabilizing activity, whereas Pa(2-19) showed poor membrane-binding and -permeabilizing activities. The results indicate that the basic residue at the N-terminal is essential for the membrane-binding activity of parasin I, and among the membrane-binding parasin I analogs, the alpha-helical structure is necessary for the membrane-permeabilizing activity.     

CRAMP analog having potent antibiotic activity without hemolytic activity

CRAMP-18 is an 18-residue functional region, corresponding to residues 16-33 of a mouse-derived antibiotic peptide CRAMP. To develop novel antibiotic peptides possessing strong antibiotic activity against bacterial, fungal and tumor cells without hemolytic activity, three analogs of CRAMP-18 were synthesized containing either Leu- or Lys-substitution. Leu-substitution ([L(1, 8)]-CRAMP-18) in the hydrophobic helix face of CRAMP-18 induced a dramatic increase in antibiotic activity without a significant increase in hemolytic activity. Lys-substitution ([K(2, 13)]-CRAMP-18 or [K(9, 16)]-CRAMP-18) in the hydrophilic helix face produced a smaller response. Therefore, [L(1, 8)]-CRAMP-18 may be an attractive candidate for developing novel peptide antibiotics.     

Impact of single-residue mutations on the structure and function of ovispirin/novispirin antimicrobial peptides

We studied three model antibacterial peptides that resembled the N-terminal 18 amino acids of SMAP-29, an alpha-helical, antimicrobial peptide of sheep. Although the parent compound, ovispirin-1 (KNLRR IIRKI IHIIK KYG), was potently antimicrobial, it was also highly cytotoxic to human epithelial cells and hemolytic for human erythrocytes. Single residue substitutions to ovispirin-1 yielded two substantially less cytotoxic peptides (novispirins), with intact antimicrobial properties. One of these, novispirin G-10, differed from ovispirin-1 only by containing glycine at position 10, instead of isoleucine. The other, novispirin T-7, contained threonine instead of isoleucine at position 7. We determined the three-dimensional solution structures of all three peptides by circular dichroism spectroscopy and two-dimensional nuclear magnetic resonance spectroscopy. Although all retained an amphipathic helical structure in 2,2,2-trifluoroethanol, they manifested subtle fine-structural changes that evidently impacted their activities greatly. These findings show that simple structural modifications can 'fine-tune' an antimicrobial peptide to minimize unwanted cytotoxicity while retaining its desired activity.     

A short α-helical antimicrobial peptide with antibacterial selectivity

A 13-residue alpha-helical peptide (K6L5WP), designed from Leu6-->Pro substitution of a hemolytic alpha-helical peptide (K6L6W), exhibited strong antibacterial activity (MIC: 2 to approximately 4 microM against three gram-positives and three gram-negatives) comparable to that of melittin but had no hemolytic activity. Tryptophan fluorescence studies indicated bacterial selectivity of K6L5WP is closely related to the selective interaction with negatively charged phospholipids on the surface of bacterial cells. These results suggested that the central Pro6 in K6L5WP plays an important role in its bacterial cell selectivity. In conclusion, K6L5WP with antibacterial selectivity may serve as an attractive candidate for the development of antimicrobial agents.     

Antimicrobial properties of the frog skin peptide, ranatuerin-1 and its [Lys-8]-substituted analog

The predicted conformation of ranatuerin-1 (SMLSVLKNLG(10)KVGLGFVACK(20)INK QC), an antimicrobial peptide first isolated from the skin of the bullfrog Rana catesbeiana, comprises three structural domains: alpha-helix (residues 1-8), beta-sheet (residues 11-16) and beta-turn (residues 20-25). Circular dichroism studies confirm significant alpha-helical character in 50% trifluoroethanol. Replacement of Cys-19 and Cys-25 by serine resulted only in decreased antimicrobial potency but deletion of either the cyclic heptapeptide region [residues (19-25)] or the N-terminal domain [residues (1-8)] produced inactive analogs. Substitution of the glycine residues in the central domain of the [Ser-19, Ser-25] analog by lysine produced inactive peptides despite increased alpha-helical content and cationicity. The substitution Asn-8-->Lys gave a ranatuerin-1 analog with increased alpha-helicity and cationicity and increased potency against a range of Gram-positive and Gram-negative bacteria and against C. albicans but only a small increase (21%) in hemolytic activity. In contrast, increasing alpha-helicity and hydrophobicity by the substitution Asn-22-->Ala resulted in a 3.5-fold increase in hemolytic activity. Effects on antimicrobial potencies of substitutions of neutral amino acids at positions 4, 18, 22, and 24 by lysine were less marked. Strains of pathogenic E. coli from different groups showed varying degrees of sensitivity to ranatuerin-1 (MIC between 5 and 40 microM) but [Lys-8] ranatuerin-1 showed increased potency (between 2- and 8-fold; P < 0.01) against all strains. The data demonstrate that [Lys-8] ranatuerin-1 shows potential as a candidate for drug development.     

复合抗菌肽PL在毕赤酵母中的分泌表达及其活性研究

为了获得抗菌活性较强的抗菌肽,将几种抗菌肽串联起来在毕赤酵母中表达,并比较其与单独抗菌肽的抑菌活性。以GenBank中的Protegrin-1(PG-1)、ScorpionDefensin(SD)、Metalnikowin-2A和SheepMyeloidAntibacterialPeptide(SMAP-29)(序列号分别为AAB27599,AAAB27538、P80409和P49928)成熟肽段作为模板序列,根据巴斯德毕赤氏酵母(P.pastoris)偏好密码子,设计并人工合成复合抗菌肽pl基因,同时用SOE法获得ScorpionDefensin的基因,分别克隆到pPICZαA载体中,转化P.pastoris受体菌X-33,在醇氧化酶(AOX)启动子调控下,复合抗菌肽PL及SD均获得表达。体外抑菌试验检测复合抗菌肽PL与单独的蝎子防御素SD的热稳定性、酸稳定性、最低抑菌浓度等,结果显示复合抗菌肽PL及SD具有很强的热酸稳定性,而针对不同的细菌,复合抗菌肽则表现出了强于单独的SD的活性,特别是对大肠杆菌。上述结果说明了该复合抗菌肽具有很好的开发前景。     

Flavinylation of the precursor of mitochondrial dimethylglycine dehydrogenase by intact and solubilised mitochondria

Tobacco plants were engineered to express SMAP-29, a mammalian antimicrobial peptide of innate immunity, as fusion protein with modified vacuolar membrane ATPase intein. The peptide was purified taking advantage of the intein-mediated self-cleaving mechanism. SMAP-29 was immunologically detected in the chromatographic eluate and appeared tightly bound to copurified plant proteins. Electrophoretic separation under disaggregating conditions indicated that the recombinant peptide was cleaved off by intein at the expected site and an overlay gel assay demonstrated that the peptide retained antimicrobial activity. These results indicate that a modified intein expression system can be used to produce pharmaceutical peptides in transgenic plants.     

Expression of SMAP-29 cathelicidin-like peptide in bacterial cells by intein-mediated system

In this work, the intein fusion approach was used for expression and purification of cathelicidin-like peptide SMAP-29 from Escherichia coli cultures. To overcome the high toxicity of the antimicrobial peptide against host cells, both C- and N-terminal fusions with Sce VMA intein were evaluated. The fusion of SMAP-29 with the N-terminus of intein had a dramatic lethal effect. In contrast, chimeric constructs harboring SMAP-29 linked to the C-terminus of intein displayed no significant inhibition of bacterial growth. Expression of intein-SMAP fusion protein was then induced in ER2566 E. coli strain by IPTG addition and different experimental conditions were tested in order to optimize the recovery of the soluble protein complex. Peptide purification was carried out by affinity chromatography: the chitin binding domain linked to intein was used to immobilize the chimeric protein on a chitin column and intein-mediated splicing of target peptide was obtained by thiol addition. Microbroth dilution assay showed that recombinant SMAP-29 displayed a high, dose-dependent bactericidal activity. These data demonstrate that the fusion of SMAP-29 with C-intein was able to inactivate the antimicrobial properties of the cathelicidin peptide allowing the expression of fusion protein in the host cell. The intein-mediated purification supplied an effective way to recover the fusion partner in its proper biologically active form.     

Antibacterial synergism of novel antibiotic peptides with chloramphenicol

HP (2-20) is an antimicrobial sequence derived from the N-terminus of Helicobacter pylori ribosomal protein L1. We previously tested whether several analogues of HP (2-20), with amino acid substitutions that increased or decreased net hydrophobicity, could be useful as therapeutic agents. In the present study, we show that substituting Gln and Asp for Trp at positions 17 and 19, respectively, of HP (2-20) (peptide A3) had potent antibacterial activity in minimal inhibition concentration and minimal bactericidal concentration without having hemolytic activity. In contrast, when we decreased hydrophobicity by substituting Leu or Phe for Ser at positions 12 and 19, respectively, of HP (2-20) (Anal 4, Anal 5), there was no significant effect on antibacterial activity. We found that A3 acted synergistically with chloramphenicol against bacterial cells. Fluorescence activated flow cytometry showed that A3-treated cells had higher fluorescence intensity than untreated cells, similar to that of melittin-treated cells. Furthermore, A3 caused significant morphological alterations of Staphylococcus aureus and Pseudomonas aeruginosa, as shown by scanning electron microscopy. Our results suggest that peptide A3 may be useful for the design of novel antibiotic peptides that possess high bacterial cell selectively and synergistic effects with conventional antibiotic agents but lack hemolytic activity.     

Antibiotic activity and structural analysis of the scorpion-derived antimicrobial peptide IsCT and its analogs

IsCT is a non-cell-selective antimicrobial peptide isolated from the scorpion Opisthacanthus madagascariensis that has potent cytolytic activity against both mammalian and bacterial cells. To investigate the structure-activity relationships of IsCT and to design novel peptide antibiotics with bacterial cell selectivity, we synthesized several analogs of IsCT and determined their three-dimensional structures in solution by 2D-NMR spectroscopy. IsCT has a linear alpha-helical structure from Gly3 to Phe13, and [K7]-IsCT has a linear alpha-helical structure from Leu2 to Phe13. [K7, P8, K11]-IsCT, which has a bend in its middle region, exhibited the highest antibacterial activity without hemolytic activity, suggesting that its proline-induced bend is an important determinant of this selectivity. Tryptophan fluorescence showed that the high selectivity of [K7, P8, K11]-IsCT toward bacterial cells is closely correlated with its highly selective interaction with negatively charged phospholipids. Its potent activity against antibiotic-resistant bacteria suggests that [K7, P8, K11]-IsCT may serve as a promising lead candidate in the development of new peptide antibiotics.     

Thermolysin-linearized microcin J25 retains the structured core of the native macrocyclic peptide and displays antimicrobial activity.

Microcin J25 (MccJ25) is the single macrocyclic antimicrobial peptide belonging to the ribosomally synthesized class of microcins that are secreted by Enterobacteriaceae. It showed potent antibacterial activity against several Salmonella and Escherichia strains and exhibited a compact three-dimensional structure [Blond et al. (2001) Eur. J. Biochem., 268, 2124-2133]. The molecular mechanisms involved in the biosynthesis, folding and mode of action of MccJ25 are still unknown. We have investigated the structure and the antimicrobial activity of thermolysin-linearized MccJ25 (MccJ25-L1-21: VGIGTPISFY10GGGAGHVPEY20F), as well as two synthetic analogs, sMccJ25-L1-21 (sequence of the thermolysin-cleaved MccJ25) and sMccJ25-L12-11 (C-terminal sequence of the MccJ25 precursor: G12GAGHVPEYF21V1GIGTPISFYG11). The three-dimensional solution structure of MccJ25-L1-21, determined by two-dimensional NMR, consists of a boot-shaped hairpin-like well-defined 8-19 region flanked by disordered N and C termini. This structure is remarkably similar to that of cyclic MccJ25, and includes a short double-stranded antiparallel beta-sheet (8-10/17-19) perpendicular to a loop (Gly11-His16). The thermolysin-linearized MccJ25-L1-21 had antibacterial activity against E. coli and S. enteritidis strains, while both synthetic analogues lacked activity and organized structure. We show that the 8-10/17-19 beta-sheet, as well as the Gly11-His16 loop are required for moderate antibacterial activity and that the Phe21-Pro6 loop and the MccJ25 macrocyclic backbone are necessary for complete antibacterial activity. We also reveal a highly stable 8-19 structured core present in both the native MccJ25 and the thermolysin-linearized peptide, which is maintained under thermolysin treatment and resists highly denaturing conditions.     

Mechanisms of action of ostrich beta-defensins against Escherichia coli

To understand their mechanism of antimicrobial activity against Gram-negative bacteria, ostrich beta-defensins, ostricacins-1 and 2 (Osp-1 and Osp-2), were compared with those of sheep myeloid antimicrobial peptide (SMAP)-29 and human neutrophil peptide (HNP)-1, well-characterized sheep alpha-helical and human alpha-defensin peptides, respectively. Fluorescence-based biochemical assays demonstrated that the ostricacins bound lipopolysaccharides and disrupted both outer and cytoplasmic membrane integrity. The ostricacins' permeabilizing ability was weaker than that of SMAP-29, but stronger than HNP-1. As ostricacins have previously shown the ability to inhibit bacterial growth, these peptides were suggested to be bacteriostatic to Gram-negative bacteria, which are caused by the interaction between the peptides and cytoplasmic targets causing the inhibition of DNA, RNA, and protein synthesis as well as enzymatic activities. These findings indicated promising possibilities for the peptides to be used in the development of therapeutic and topical products.     

Structure-activity relationship of HP (2-20) analog peptide: enhanced antimicrobial activity by N-terminal random coil region deletion

HP (2-20) (AKKVFKRLEKLFSKIQNDK) is a 19-aa antimicrobial peptide derived from N-terminus of Helicobacter pylori Ribosomal protein L1 (RpL1). In the previous study, several analogs with amino acid substitutions were designed to increase or decrease only the net hydrophobicity. In particular, substitutions of Gln(16) and Asp(18) with Trp (Anal 3) for hydrophobic amino acid caused a dramatic increase in antibiotic activity without a hemolytic effect. HP-A3 is a potent antimicrobial peptide that forms, in a hydrophobic medium, an amphipathic structure consisting of an N-terminal random coil region (residues 2-5) and extended C-terminal regular alpha-helical region (residues 6-20). To obtain the short and potent alpha-helical antimicrobial peptide, we synthesized a N-terminal random coil deleted HP-A3 (A3-NT) and examined their antimicrobial activity and mechanism of action. The resulting 15mer peptide showed increased antibacterial and antifungal activity to 2- and 4-fold, respectively, without hemolysis. Confocal fluorescence microscopy studies showed that A3-NT was accumulated in the plasma membrane. Flow cytometric analysis revealed that A3-NT acted in salt- and energy-independent manner. Furthermore, A3-NT causes significant morphological alterations of the bacterial surfaces as shown by scanning electron microscopy. Circular dichroism (CD) analysis revealed that A3-NT showed higher alpha-helical contents than the HP-A3 peptide in 50% TFE solution. Therefore, the cell-lytic efficiency of HP-A3, which depended on the alpha-helical content of peptide, correlated linearly with their antimicrobial potency.     

β-发卡抗菌肽的全新设计及其生物学活性

通过缬氨酸和精氨酸的交替连接形成β-发卡结构的两条侧链,D-脯氨酸和甘氨酸形成β-转角单元以及侧链末端的两个半胱氨酸连接形成一个二硫键,来设计得到全新的由16残基构成的β-发卡抗菌肽VR。对设计得到的抗菌肽VR的生物学活性进行了检测,主要测定了新型β-发卡抗菌肽VR的最小杀菌浓度、对红细胞的溶血活性、杀菌动力学和盐敏感性。结果发现,VR和蜂毒素具有相似的杀菌活性,而溶血活性远低于蜂毒素,这表明VR比蜂毒素具有更高的细胞选择性。在NaCl的浓度低于100 mmol/L时,VR的杀菌活性没有受到影响;在NaCl的浓度为100 mmol/L时,VR具有50%的杀菌活性。综上可见,VR具有较优异的生物学活性,拥有成为抗生素替代物的发展潜力。