Davuluri Kusuma Sai, Singh Amit Kumar, Singh Ajay Vir, Chaudhary Pooja, Raman Sunil Kumar, Kushwaha Shweta, Singh Shoor Vir, Chauhan Devendra Singh
Department of Microbiology and Molecular Biology, ICMR, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, India.
Division of Pharmaceutics and Pharmacokinetics, CSIR, Central Drug Research Institute, Lucknow, India.
Microbiol Spectr. 2023 Jan 31;11(2):e0319722. doi: 10.1128/spectrum.03197-22.
The majority of preclinical research has shown that Mycobacterium tuberculosis can modify host lipids in various ways. To boost its intramacrophage survival, M. tuberculosis causes host lipids to build up, resulting in the development of lipid-laden foam cells. M. tuberculosis binds to and enters the macrophage via the cell membrane cholesterol. Aggregation of cholesterol in the cell wall of M. tuberculosis and an increase in vascularity at the granuloma site reduce the permeability of rifampicin and isoniazid concentrations. However, very few studies have assessed the effect of statins on drug penetration. Here, we used atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, to observe its effect on the bacterial burden by increasing the drug concentration at the infection site. We looked into how atorvastatin could be used in conjunction with first-line drugs to promote drug permeation. In this study, we detected an accumulation of drugs at the peripheral sites of the lungs and impaired drug distribution to the diseased sites. The efficacy of antituberculosis drugs, with atorvastatin as an adjunct, on the viability of M. tuberculosis cells was demonstrated. A nontoxic statin dosage established phenotypic and normal granuloma vasculature and showed an additive effect with rifampicin and isoniazid. Our data show that statins help to reduce the tuberculosis bacterial burden. Our findings reveal that the bacterial load is connected with impaired drug permeability resulting from lipid accumulation in the bacterial cell wall. Statin therapy combined with antituberculosis medications have the potential to improve treatment in tuberculosis patients. Mycobacterium tuberculosis binds to and enters the macrophage via the cell membrane cholesterol. M. tuberculosis limits phagosomal maturation and activation without engaging in phagocytosis. Aggregation of cholesterol in the cell wall of M. tuberculosis and an increase in the vascularity at the granuloma site reduce the permeability of rifampicin and isoniazid concentrations. However, very few studies have assessed the effect of statins on drug penetration, which can be increased through a reduction in cholesterol and vascularity. Herein, we used atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, to observe its effect on bacterial burden through increasing the drug concentration at the infection site. Our main research goal is to diminish mycobacterial dissemination and attenuate bacterial growth by increasing drug permeability.
大多数临床前研究表明，结核分枝杆菌可通过多种方式改变宿主脂质。为提高其在巨噬细胞内的存活率，结核分枝杆菌会导致宿主脂质积聚，进而形成富含脂质的泡沫细胞。结核分枝杆菌通过细胞膜胆固醇与巨噬细胞结合并进入细胞。结核分枝杆菌细胞壁中胆固醇的聚集以及肉芽肿部位血管增多会降低利福平和平浓度的通透性。然而，很少有研究评估他汀类药物对药物渗透的影响。在此，我们使用阿托伐他汀，一种3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，通过提高感染部位的药物浓度来观察其对细菌负荷的影响。我们研究了阿托伐他汀如何与一线药物联合使用以促进药物渗透。在本研究中，我们检测到肺部外周部位药物积聚，且药物向患病部位的分布受损。证明了以阿托伐他汀为辅助药物的抗结核药物对结核分枝杆菌细胞活力的疗效。无毒的他汀类药物剂量建立了表型和正常的肉芽肿血管，并与利福平和异烟肼显示出相加作用。我们的数据表明，他汀类药物有助于降低结核细菌负荷。我们的研究结果表明，细菌负荷与细菌细胞壁脂质积聚导致的药物通透性受损有关。他汀类药物治疗与抗结核药物联合使用有可能改善结核病患者的治疗效果。结核分枝杆菌通过细胞膜胆固醇与巨噬细胞结合并进入细胞。结核分枝杆菌在不进行吞噬作用的情况下限制吞噬体成熟和激活。结核分枝杆菌细胞壁中胆固醇的聚集以及肉芽肿部位血管增多会降低利福平和平浓度的通透性。然而，很少有研究评估他汀类药物对药物渗透的影响，而这可通过降低胆固醇和血管来增加。在此，我们使用阿托伐他汀，一种3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，通过提高感染部位的药物浓度来观察其对细菌负荷的影响。我们的主要研究目标是通过增加药物通透性来减少分枝杆菌传播并减弱细菌生长。
