Nisin抗菌肽抑制致龋菌和根管感染致病菌的体外研究
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摘要
由于细菌对抗生素的耐药性问题越来越严重，目前越来越多的人正在关注抗菌肽作用。Nisin抗菌肽是由益生菌乳酸链球菌(L. lactis)产生的34个氨基酸的多肽，具有很多优良的特性，是目前研究最为广泛的硫醚抗生素。然而目前有关nisin对口腔致病菌的作用研究报导较少。本研究我们着重对nisin抑制口腔致病菌的特性及其可能的机理进行了研究。
首先，乳酸链球菌首次被引用抑制口腔中主要致龋菌变异链球菌(S.mutans)。我们发现乳酸链球菌在营养不足时可以竞争性抑制变链菌生长，并且变链菌代谢产物，包括一些外源性信号分子可以增强乳酸链球菌中nisin合成相关基因的表达。乳酸链球菌可以有效地粘附在牙釉质表面，但是对牙釉质表面侵蚀程度明显比变链菌小。第二，在最小抑菌浓度、最小杀菌浓度和Spot-on-lawn检测中，nisin对9种常见的致龋菌显示出了不同的抗菌作用，并且唾液中成份对nisin的抗菌性没有影响。此外场发射扫描电镜显示血链球菌、变链菌、发酵乳杆菌和嗜酸乳杆菌经过nisin处理后其形态和胞膜均受到不同程度的破坏。第三，在nisin和氟化钠或洗必泰协同性抑制变链菌的检测中，通过棋盘法、部分抑菌浓度、部分杀菌浓度检测，我们发现nisin和氟化钠具有协同性抑制变链菌的作用，而nisin和洗必泰则不具有协同性。在时间杀死研究中，变链菌经过nisin和氟化钠联合处理后，细菌生存率明显下降。场发射扫描电镜显示在不同药物单独或联合处理中，nisin和氟化钠对变链菌破坏程度是最显著的。此外，在抗变链菌生物膜检测中，氟化钠联合nisin对4h和16h的变链菌生物膜的作用比氟化钠单独作用显示出更强破坏能力。这些研究结果表明，乳酸链球菌和抗菌肽nisin在抑制口腔致龋菌和预防龋病发生中具有良好的应用前景。
MTAD (A mixture of tetracycline isomer, acid and detergent,一种四环类类药物、酸和去污剂的混合物)是良好的根管冲洗剂，在MTADN(MTAD联合nisin)对与牙髓感染有密切相关的9种致病菌抑制研究中，MTADN显示出快速和明显的抗菌作用。粪肠球菌(E. faecalis)是引起继发性和持续性牙髓感染的主要致病菌，在抑制粪肠球菌作用中，我们利用棋盘法和部分抑菌浓度检测了nisin和常用根管冲洗液MTAD的协同抗菌作用，结果显示nisin可以显著提高MTAD对粪肠球菌抑菌作用。MTADN对粪肠球菌最小抑菌浓度比MTAD和MTAN(用nisin代替MTAD中的多西霉素)低。当多西霉素和nisin联合应用时，nisin对细菌胞膜形成的孔洞可以有利于多西霉素分子进入到细菌胞内，更好发挥抗菌作用，因而nisin和多西霉素结合具有协同性抑制粪肠球菌的作用。场发射扫描电镜也显示MTADN对粪肠球菌破坏程度最为明显。这些研究结果表明nisin和MTAD联合应用，作为根管冲洗液，可以有效清除根管内的致病菌。
More attention has increasingly been paid to the antibacterial peptide dueto bacterial resistance to some common antibiotics. Nisin, a34-residue peptideproduced by Lactococcus lactis, is emerged as one of the most extensivelystudied lantibiotics and possess many excellent properties. However, to ourknowledge, it appears to be no report that nisin was used to inhibit pathogens inoral cavity. In the present study, the antibacterial peptide nisin is considered toinhibit pathogens in oral cavity.
Firstly, the probiotic L. lactis was first used to inhibit the major cariogenicbacterium Streptococcus mutans. We found that L. lactis competitively inhibitedS. mutans growth under nutritional deficiency, and the metabolites of S. mutans,including several exogenous molecular signals, enhanced the expression ofgenes related to nisin synthesis in L. lactis. Additionally, L. lactis effectivelycolonized the surface of tooth enamel, which showed substantially less decaywith L. lactis adhesion compared to S. mutans adhesion. Secondly, in theminimal inhibitory concentration (MIC) and minimal bactericide concentration (MBC) and spot-on-lawn assay, nisin displayed different antimicrobial activityagainst the nine cariogenic bacteria. The antibacterial activity of nisin was notaffected by ingredient in saliva. Furthermore, morphology and membranes ofStreptococcus sanguinis, Streptococcus mutans, Lactobacillus fermenti andLactobacillus acidophilus with nisin treatment were observed and showeddifferent degrees of damage by a Field Emission Scanning Electron Microscope(FE-SEM). Thirdly, in an in vitro synergetic evaluation of nisin and sodiumfluoride or chlorhexidine against S mutans, a synergetic effect on S. mutans wasfound between nisin and sodium fluoride, but there was no interaction betweennisin and chlorhexidine by the checkerboard, the fractional inhibitoryconcentration (FIC) and the fractional bactericidal concentration (FBC) tests. S.mutans survival rates showed a significant decline after treatment with acombination of nisin and sodium fluoride in a time-kill study. FE-SEM showedthat the damage to S. mutans with the combined nisin and sodium fluoridetreatment was the most severe among all of the different single and combinedantimicrobial treatments. Furthermore, in the antibiofilm test, nisin incombination with sodium fluoride produced a stronger bactericidal effect on a S.mutans biofilm for4h and16h compared with sodium fluoride alone byconfocal laser scanning microscopy. The studies indicate that the probiotic Llactis and antibacterial peptide nisin have the potential to be new methods toinhibit cariogenic bacteria in oral cavity and prevent dental caries..
MTAD (A mixture of tetracycline isomer, acid and detergent) is a higheffective intracanal irrigant. In the study of MTADN (nisin in combination withMTAD) against nisin common pathogens associated with dental pulp and rootcanal infection, MTADN showed a strong and rapid antibacterial activity. In thestudy of inhibtion of E. faecalis associated with the secondary and persistent root canal infection, the synergetic action between nisin and a commonintracanal irrigant, MTAD was evaluated by checkerboard and FIC, and theresult showed that nisin can markedly improve the bactericidal effect of MTADon E. faecalis. The MBC of MTADN against E. faecalis was lower than that ofMTAD and MTAN (substitution of doxycycline in MTAD with nisin). Whendoxycycline is applied in combination with nisin, the pores formed by nisin onthe surface of the cell membrane can facilitate the penetration of doxycyclinemolecules into the microorganism and exert its antibacterial role, and therebythe combination of nisin and doxycycline had a significantly synergeticantibacterial effect on E. faecalis. The morphological modification of FE-SEMalso showed that the most damage on E. faecalis was found with the treatmentof MTADN. The studies indicate that the drugs combination between nisin andMTAD has the potential to be as an effective intracanal irrigant.
首先，乳酸链球菌首次被引用抑制口腔中主要致龋菌变异链球菌(S.mutans)。我们发现乳酸链球菌在营养不足时可以竞争性抑制变链菌生长，并且变链菌代谢产物，包括一些外源性信号分子可以增强乳酸链球菌中nisin合成相关基因的表达。乳酸链球菌可以有效地粘附在牙釉质表面，但是对牙釉质表面侵蚀程度明显比变链菌小。第二，在最小抑菌浓度、最小杀菌浓度和Spot-on-lawn检测中，nisin对9种常见的致龋菌显示出了不同的抗菌作用，并且唾液中成份对nisin的抗菌性没有影响。此外场发射扫描电镜显示血链球菌、变链菌、发酵乳杆菌和嗜酸乳杆菌经过nisin处理后其形态和胞膜均受到不同程度的破坏。第三，在nisin和氟化钠或洗必泰协同性抑制变链菌的检测中，通过棋盘法、部分抑菌浓度、部分杀菌浓度检测，我们发现nisin和氟化钠具有协同性抑制变链菌的作用，而nisin和洗必泰则不具有协同性。在时间杀死研究中，变链菌经过nisin和氟化钠联合处理后，细菌生存率明显下降。场发射扫描电镜显示在不同药物单独或联合处理中，nisin和氟化钠对变链菌破坏程度是最显著的。此外，在抗变链菌生物膜检测中，氟化钠联合nisin对4h和16h的变链菌生物膜的作用比氟化钠单独作用显示出更强破坏能力。这些研究结果表明，乳酸链球菌和抗菌肽nisin在抑制口腔致龋菌和预防龋病发生中具有良好的应用前景。
MTAD (A mixture of tetracycline isomer, acid and detergent,一种四环类类药物、酸和去污剂的混合物)是良好的根管冲洗剂，在MTADN(MTAD联合nisin)对与牙髓感染有密切相关的9种致病菌抑制研究中，MTADN显示出快速和明显的抗菌作用。粪肠球菌(E. faecalis)是引起继发性和持续性牙髓感染的主要致病菌，在抑制粪肠球菌作用中，我们利用棋盘法和部分抑菌浓度检测了nisin和常用根管冲洗液MTAD的协同抗菌作用，结果显示nisin可以显著提高MTAD对粪肠球菌抑菌作用。MTADN对粪肠球菌最小抑菌浓度比MTAD和MTAN(用nisin代替MTAD中的多西霉素)低。当多西霉素和nisin联合应用时，nisin对细菌胞膜形成的孔洞可以有利于多西霉素分子进入到细菌胞内，更好发挥抗菌作用，因而nisin和多西霉素结合具有协同性抑制粪肠球菌的作用。场发射扫描电镜也显示MTADN对粪肠球菌破坏程度最为明显。这些研究结果表明nisin和MTAD联合应用，作为根管冲洗液，可以有效清除根管内的致病菌。
More attention has increasingly been paid to the antibacterial peptide dueto bacterial resistance to some common antibiotics. Nisin, a34-residue peptideproduced by Lactococcus lactis, is emerged as one of the most extensivelystudied lantibiotics and possess many excellent properties. However, to ourknowledge, it appears to be no report that nisin was used to inhibit pathogens inoral cavity. In the present study, the antibacterial peptide nisin is considered toinhibit pathogens in oral cavity.
Firstly, the probiotic L. lactis was first used to inhibit the major cariogenicbacterium Streptococcus mutans. We found that L. lactis competitively inhibitedS. mutans growth under nutritional deficiency, and the metabolites of S. mutans,including several exogenous molecular signals, enhanced the expression ofgenes related to nisin synthesis in L. lactis. Additionally, L. lactis effectivelycolonized the surface of tooth enamel, which showed substantially less decaywith L. lactis adhesion compared to S. mutans adhesion. Secondly, in theminimal inhibitory concentration (MIC) and minimal bactericide concentration (MBC) and spot-on-lawn assay, nisin displayed different antimicrobial activityagainst the nine cariogenic bacteria. The antibacterial activity of nisin was notaffected by ingredient in saliva. Furthermore, morphology and membranes ofStreptococcus sanguinis, Streptococcus mutans, Lactobacillus fermenti andLactobacillus acidophilus with nisin treatment were observed and showeddifferent degrees of damage by a Field Emission Scanning Electron Microscope(FE-SEM). Thirdly, in an in vitro synergetic evaluation of nisin and sodiumfluoride or chlorhexidine against S mutans, a synergetic effect on S. mutans wasfound between nisin and sodium fluoride, but there was no interaction betweennisin and chlorhexidine by the checkerboard, the fractional inhibitoryconcentration (FIC) and the fractional bactericidal concentration (FBC) tests. S.mutans survival rates showed a significant decline after treatment with acombination of nisin and sodium fluoride in a time-kill study. FE-SEM showedthat the damage to S. mutans with the combined nisin and sodium fluoridetreatment was the most severe among all of the different single and combinedantimicrobial treatments. Furthermore, in the antibiofilm test, nisin incombination with sodium fluoride produced a stronger bactericidal effect on a S.mutans biofilm for4h and16h compared with sodium fluoride alone byconfocal laser scanning microscopy. The studies indicate that the probiotic Llactis and antibacterial peptide nisin have the potential to be new methods toinhibit cariogenic bacteria in oral cavity and prevent dental caries..
MTAD (A mixture of tetracycline isomer, acid and detergent) is a higheffective intracanal irrigant. In the study of MTADN (nisin in combination withMTAD) against nisin common pathogens associated with dental pulp and rootcanal infection, MTADN showed a strong and rapid antibacterial activity. In thestudy of inhibtion of E. faecalis associated with the secondary and persistent root canal infection, the synergetic action between nisin and a commonintracanal irrigant, MTAD was evaluated by checkerboard and FIC, and theresult showed that nisin can markedly improve the bactericidal effect of MTADon E. faecalis. The MBC of MTADN against E. faecalis was lower than that ofMTAD and MTAN (substitution of doxycycline in MTAD with nisin). Whendoxycycline is applied in combination with nisin, the pores formed by nisin onthe surface of the cell membrane can facilitate the penetration of doxycyclinemolecules into the microorganism and exert its antibacterial role, and therebythe combination of nisin and doxycycline had a significantly synergeticantibacterial effect on E. faecalis. The morphological modification of FE-SEMalso showed that the most damage on E. faecalis was found with the treatmentof MTADN. The studies indicate that the drugs combination between nisin andMTAD has the potential to be as an effective intracanal irrigant.
引文
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