Auckland Bioengineering Institute, University of Auckland, Auckland, NZ.
Department of Molecular Medicine and Pathology, University of Auckland, Auckland, NZ.
PLoS One. 2022 Aug 12;17(8):e0273088. doi: 10.1371/journal.pone.0273088. eCollection 2022.
The rise in antibiotic resistance has stimulated research into adjuvants that can improve the efficacy of broad-spectrum antibiotics. Lactoferrin is a candidate adjuvant; it is a multifunctional iron-binding protein with antimicrobial properties. It is known to show dose-dependent antimicrobial activity against Staphylococcus aureus through iron sequestration and repression of β-lactamase expression. However, S. aureus can extract iron from lactoferrin through siderophores for their growth, which confounds the resolution of lactoferrin's method of action. We measured the minimum inhibitory concentration (MIC) for a range of lactoferrin/ β-lactam antibiotic dose combinations and observed that at low doses (< 0.39 μM), lactoferrin contributes to increased S. aureus growth, but at higher doses (> 6.25 μM), iron-depleted native lactoferrin reduced bacterial growth and reduced the MIC of the β-lactam-antibiotic cefazolin. This differential behaviour points to a bacterial population response to the lactoferrin/ β-lactam dose combination. Here, with the aid of a mathematical model, we show that lactoferrin stratifies the bacterial population, and the resulting population heterogeneity is at the basis of the dose dependent response seen. Further, lactoferrin disables a sub-population from β-lactam-induced production of β-lactamase, which when sufficiently large reduces the population's ability to recover after being treated by an antibiotic. Our analysis shows that an optimal dose of lactoferrin acts as a suitable adjuvant to eliminate S. aureus colonies using β-lactams, but sub-inhibitory doses of lactoferrin reduces the efficacy of β-lactams.
抗生素耐药性的上升刺激了人们对佐剂的研究，这些佐剂可以提高广谱抗生素的疗效。乳铁蛋白是一种候选佐剂；它是一种具有抗菌特性的多功能铁结合蛋白。已知它通过铁螯合和抑制β-内酰胺酶表达，对金黄色葡萄球菌表现出剂量依赖性的抗菌活性。然而，金黄色葡萄球菌可以通过铁载体从乳铁蛋白中提取铁来生长，这使得乳铁蛋白的作用机制难以解决。我们测量了一系列乳铁蛋白/β-内酰胺抗生素剂量组合的最低抑菌浓度（MIC），并观察到在低剂量（<0.39 μM）下，乳铁蛋白促进金黄色葡萄球菌的生长，但在高剂量（>6.25 μM）下，铁耗尽的天然乳铁蛋白会减少细菌生长并降低β-内酰胺抗生素头孢唑林的 MIC。这种差异行为表明了细菌种群对乳铁蛋白/β-内酰胺剂量组合的反应。在这里，借助数学模型，我们表明乳铁蛋白使细菌种群分层，并且由此产生的种群异质性是观察到的剂量依赖性反应的基础。此外，乳铁蛋白使细菌亚群无法产生β-内酰胺酶，从而在抗生素治疗后降低了细菌种群的恢复能力。我们的分析表明，乳铁蛋白的最佳剂量可以作为β-内酰胺的合适佐剂来消除金黄色葡萄球菌菌落，但亚抑制剂量的乳铁蛋白会降低β-内酰胺类抗生素的疗效。
