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Abstract：
UNASSIGNED: The emergence and rapid spread of multi-drug resistant (MDR) bacterial strains, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), have posed a significant challenge to the medical community due to their ability to form biofilm and develop resistance to common antibiotics. Traditional antibiotics that were once effective in treating bacterial infections are now becoming increasingly ineffective, leading to severe consequences for patient outcomes. This concerning situation has called for urgent research to explore alternative treatment strategies. Recent studies have shown that antimicrobial peptides (AMPs) hold promise as effective agents against biofilm-associated drug-resistant infections as well as to enhance the efficacy of conventional antibiotics. Accordingly, we aimed to investigate the antimicrobial and antibiofilm effects of melittin AMP, both alone and in combination with penicillin and oxacillin, against biofilm-forming MDR-MRSA and -VRSA.
UNASSIGNED: In this study, we investigated the kinetics of biofilm formation and assessed various parameters related to the antimicrobial and antibiofilm efficacy of melittin and antibiotics, both alone and in combination, against MDR-MRSA and -VRSA. The antimicrobial parameters included the Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), Fractional Inhibitory Concentration Index (FICi), Fractional Bactericidal Concentration Index (FBCi), and the antibiofilm activity of melittin and antibiotics indicated by the Minimum Biofilm Inhibitory Concentration (MBIC), Minimal Biofilm Eradication Concentration (MBEC), Fractional Biofilm Inhibitory Concentration Index (FBICi), and Fractional Biofilm Eradication Concentration Index (FBECi).
UNASSIGNED: The MIC results showed that all S. aureus isolates were resistant to penicillin (≥0.25 μg/mL), and 66% of isolates were resistant to oxacillin. The geometric means of the MIC values for penicillin, oxacillin, and melittin were 19.02, 16, and 1.62 μg/ml, respectively, and the geometric means of the MBC values for penicillin, oxacillin, and melittin were 107.63, 49.35, and 5.45 μg/ml, respectively. The study revealed that the combination indexes of melittin-penicillin and melittin-oxacillin, as determined by FIC values against all isolates, were 0.37 and 0.03, respectively. Additionally, melittin-penicillin and melittin-oxacillin exhibited combination indexes based on FBC values against all isolates at 1.145 and 0.711, respectively. Besides, melittin inhibited the biofilm formation of all S. aureus isolates, with MBIC values ranging from 10 to 1.25 μg/mL, and MBEC values ranging from 40 to 10 μg/mL. Generally, the combination indexes of melittin-penicillin and melittin-oxacillin, determined using FBIC values against all isolates, were 0.23 and 0.177, respectively. Moreover, melittin-penicillin and melittin-oxacillin typically had combination indexes based on FBEC values against all isolates at 5 and 2.97, respectively.
UNASSIGNED: In conclusion, our study provides evidence that melittin is effective against both planktonik and biofilm forms of MRSA and VRSA and exhibits significant synergistic effects when combined with antibiotics. These results suggest that melittin and antibiotics could be a potential candidate for further investigation for in vivo infections caused by MDR S. aureus. Furthermore, melittin has the potential to restore the efficacy of penicillin and oxacillin antibiotics in the treatment of MDR infections. Applying AMPs, like melittin, to revive beta-lactam antibiotics against MRSA and VRSA is an innovative approach against antibiotic-resistant bacteria. Further research is needed to optimize dosage and understand melittin mechanism and interactions with beta-lactam antibiotics for successful clinical applications.
UNASSIGNED: In this study, we investigated the kinetics of biofilm formation and assessed various parameters related to the antimicrobial and antibiofilm efficacy of melittin and antibiotics, both alone and in combination, against MDR-MRSA and -VRSA. The antimicrobial parameters included the Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), Fractional Inhibitory Concentration Index (FICi), Fractional Bactericidal Concentration Index (FBCi), and the antibiofilm activity of melittin and antibiotics indicated by the Minimum Biofilm Inhibitory Concentration (MBIC), Minimal Biofilm Eradication Concentration (MBEC), Fractional Biofilm Inhibitory Concentration Index (FBICi), and Fractional Biofilm Eradication Concentration Index (FBECi).
UNASSIGNED: The MIC results showed that all S. aureus isolates were resistant to penicillin (≥0.25 μg/mL), and 66% of isolates were resistant to oxacillin. The geometric means of the MIC values for penicillin, oxacillin, and melittin were 19.02, 16, and 1.62 μg/ml, respectively, and the geometric means of the MBC values for penicillin, oxacillin, and melittin were 107.63, 49.35, and 5.45 μg/ml, respectively. The study revealed that the combination indexes of melittin-penicillin and melittin-oxacillin, as determined by FIC values against all isolates, were 0.37 and 0.03, respectively. Additionally, melittin-penicillin and melittin-oxacillin exhibited combination indexes based on FBC values against all isolates at 1.145 and 0.711, respectively. Besides, melittin inhibited the biofilm formation of all S. aureus isolates, with MBIC values ranging from 10 to 1.25 μg/mL, and MBEC values ranging from 40 to 10 μg/mL. Generally, the combination indexes of melittin-penicillin and melittin-oxacillin, determined using FBIC values against all isolates, were 0.23 and 0.177, respectively. Moreover, melittin-penicillin and melittin-oxacillin typically had combination indexes based on FBEC values against all isolates at 5 and 2.97, respectively.
UNASSIGNED: In conclusion, our study provides evidence that melittin is effective against both planktonik and biofilm forms of MRSA and VRSA and exhibits significant synergistic effects when combined with antibiotics. These results suggest that melittin and antibiotics could be a potential candidate for further investigation for in vivo infections caused by MDR S. aureus. Furthermore, melittin has the potential to restore the efficacy of penicillin and oxacillin antibiotics in the treatment of MDR infections. Applying AMPs, like melittin, to revive beta-lactam antibiotics against MRSA and VRSA is an innovative approach against antibiotic-resistant bacteria. Further research is needed to optimize dosage and understand melittin mechanism and interactions with beta-lactam antibiotics for successful clinical applications.
摘要：
■多重耐药（MDR）细菌菌株的出现和迅速传播，如耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素金黄色葡萄球菌（VRSA），由于它们形成生物膜并对常见抗生素产生耐药性的能力，对医学界提出了重大挑战。曾经有效治疗细菌感染的传统抗生素现在变得越来越无效，对患者预后造成严重后果。这种令人担忧的情况要求进行紧急研究以探索替代治疗策略。最近的研究表明，抗微生物肽（AMP）有望作为抗生物膜相关耐药感染的有效药物以及增强常规抗生素的功效。因此，我们旨在研究蜂毒素AMP的抗菌和抗生物膜作用，单独或与青霉素和苯唑西林联合使用，对抗生物膜形成的MDR-MRSA和-VRSA。
■在这项研究中，我们研究了生物膜形成的动力学，并评估了与蜂毒素和抗生素的抗微生物和抗生物膜功效相关的各种参数，无论是单独还是组合，针对MDR-MRSA和-VRSA。抗菌参数包括最小抑制浓度（MIC），最小杀菌浓度（MBC），分数抑制浓度指数（FICi），杀菌浓度指数（FBCi），以及由最小生物膜抑制浓度（MBIC）指示的蜂毒素和抗生素的抗生物膜活性，最小生物膜消除浓度（MBEC），分数生物膜抑制浓度指数（FBICi），和分数生物膜消除浓度指数(FBECi)。
■MIC结果表明，所有金黄色葡萄球菌分离株对青霉素（≥0.25μg/mL）具有抗性，66%的菌株对苯唑西林耐药。青霉素MIC值的几何平均值，苯唑西林,蜂毒素分别为19.02、16和1.62μg/ml，分别,以及青霉素MBC值的几何平均值，苯唑西林,蜂毒素分别为107.63、49.35和5.45μg/ml，分别。研究表明，蜂毒素-青霉素和蜂毒素-苯唑西林的组合指标，根据所有分离株的FIC值确定，分别为0.37和0.03。此外,根据所有分离株的FBC值，蜂毒素-青霉素和蜂毒素-苯唑西林的组合指数分别为1.145和0.711。此外,蜂毒素抑制了所有金黄色葡萄球菌分离株的生物膜形成，MBIC值范围为10至1.25μg/mL，和MBEC值范围为40至10μg/mL。一般来说,蜂毒素-青霉素和蜂毒素-苯唑西林的组合指标，使用针对所有分离株的FBIC值确定，分别为0.23和0.177。此外，蜂毒素-青霉素和蜂毒素-苯唑西林的组合指数通常基于对所有分离株的FBEC值分别为5和2.97。
■总而言之，我们的研究提供了证据,表明蜂毒素对浮游生物和生物膜形式的MRSA和VRSA均有效,并且与抗生素联合使用时表现出显著的协同作用.这些结果表明，蜂毒素和抗生素可能是进一步研究由MDR金黄色葡萄球菌引起的体内感染的潜在候选者。此外，蜂毒素有可能恢复青霉素和苯唑西林抗生素治疗MDR感染的疗效。应用AMP,像Melittin,针对MRSA和VRSA恢复β-内酰胺类抗生素是针对抗生素耐药菌的创新方法。需要进一步的研究来优化剂量并了解蜂毒素的作用机制以及与β-内酰胺抗生素的相互作用，以成功应用于临床。
■在这项研究中，我们研究了生物膜形成的动力学，并评估了与蜂毒素和抗生素的抗微生物和抗生物膜功效相关的各种参数，无论是单独还是组合，针对MDR-MRSA和-VRSA。抗菌参数包括最小抑制浓度（MIC），最小杀菌浓度（MBC），分数抑制浓度指数（FICi），杀菌浓度指数（FBCi），以及由最小生物膜抑制浓度（MBIC）指示的蜂毒素和抗生素的抗生物膜活性，最小生物膜消除浓度（MBEC），分数生物膜抑制浓度指数（FBICi），和分数生物膜消除浓度指数(FBECi)。
■MIC结果表明，所有金黄色葡萄球菌分离株对青霉素（≥0.25μg/mL）具有抗性，66%的菌株对苯唑西林耐药。青霉素MIC值的几何平均值，苯唑西林,蜂毒素分别为19.02、16和1.62μg/ml，分别,以及青霉素MBC值的几何平均值，苯唑西林,蜂毒素分别为107.63、49.35和5.45μg/ml，分别。研究表明，蜂毒素-青霉素和蜂毒素-苯唑西林的组合指标，根据所有分离株的FIC值确定，分别为0.37和0.03。此外,根据所有分离株的FBC值，蜂毒素-青霉素和蜂毒素-苯唑西林的组合指数分别为1.145和0.711。此外,蜂毒素抑制了所有金黄色葡萄球菌分离株的生物膜形成，MBIC值范围为10至1.25μg/mL，和MBEC值范围为40至10μg/mL。一般来说,蜂毒素-青霉素和蜂毒素-苯唑西林的组合指标，使用针对所有分离株的FBIC值确定，分别为0.23和0.177。此外，蜂毒素-青霉素和蜂毒素-苯唑西林的组合指数通常基于对所有分离株的FBEC值分别为5和2.97。
■总而言之，我们的研究提供了证据,表明蜂毒素对浮游生物和生物膜形式的MRSA和VRSA均有效,并且与抗生素联合使用时表现出显著的协同作用.这些结果表明，蜂毒素和抗生素可能是进一步研究由MDR金黄色葡萄球菌引起的体内感染的潜在候选者。此外，蜂毒素有可能恢复青霉素和苯唑西林抗生素治疗MDR感染的疗效。应用AMP,像Melittin,针对MRSA和VRSA恢复β-内酰胺类抗生素是针对抗生素耐药菌的创新方法。需要进一步的研究来优化剂量并了解蜂毒素的作用机制以及与β-内酰胺抗生素的相互作用，以成功应用于临床。
