Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Histogen, San Diego, California, USA.
Drug Dev Res. 2023 Dec;84(8):1567-1571. doi: 10.1002/ddr.22099. Epub 2023 Aug 4.
Staphylococcus aureus is the leading cause of skin and soft tissue infections. With the emergence of antibiotic-resistant bacteria, there is an unmet clinical need to develop immune-based therapies to treat skin infections. Previously, we have shown pan-caspase inhibition as a potential host-directed immunotherapy against community-acquired methicillin-resistant S aureus (CA-MRSA) and other bacterial skin infections. Here, we evaluated the role of irreversible pan-caspase inhibitor emricasan as a monotherapy and an adjunctive with a standard-of-care antibiotic, doxycycline, as potential host-directed immunotherapies against S. aureus skin infections in vivo. We used the established CA-MRSA strain USA300 on the dorsum of WT C57BL/6J mice and monitored lesion size and bacterial burden noninvasively, and longitudinally over 14 days with in vivo bioluminescence imaging (BLI). Mice in four groups placebo (0.5% carboxymethyl cellulose [CMC] solution), placebo plus doxycycline (100 mg/kg), emricasan (40 mg/kg) plus doxycycline, and emricasan only were treated orally twice daily by oral gavage for 7 days, starting at 4 h after injection of S aureus. When compared with placebo, all three groups, placebo plus doxycycline, emricasan plus doxycycline, and emricasan treated group, exhibited biological effect, with reduction of both the lesion size (*p = .0277, ****p < .0001, ****p < .0001, respectively) and bacterial burden (***p = .003, ****p < .0001, ****p < .0001, respectively). Importantly, the efficacy of emricasan against S. aureus was not due to direct antibacterial activity. Collectively, pan-caspase inhibitor emricasan and emricasan plus doxycycline reduced both the lesion size and bacterial burden in vivo, and emricasan is a potential host-directed immunotherapy against MRSA skin infections in a preclinical mouse model.
金黄色葡萄球菌是皮肤和软组织感染的主要原因。随着抗生素耐药菌的出现，人们迫切需要开发基于免疫的疗法来治疗皮肤感染。此前，我们已经表明，泛半胱天冬酶抑制剂作为一种潜在的针对社区获得性耐甲氧西林金黄色葡萄球菌（CA-MRSA）和其他细菌性皮肤感染的宿主定向免疫疗法。在这里，我们评估了不可逆的泛半胱天冬酶抑制剂 emricasan 作为单一疗法以及与标准护理抗生素强力霉素联合应用作为宿主定向免疫疗法的作用，以治疗金黄色葡萄球菌皮肤感染。我们使用已建立的 CA-MRSA 菌株 USA300 在 WT C57BL/6J 小鼠的背部，并使用活体生物发光成像（BLI）非侵入性地、纵向地监测 14 天内的病变大小和细菌负荷。四组小鼠（0.5%羧甲基纤维素[CMC]溶液）、安慰剂加强力霉素（100mg/kg）、emricasan（40mg/kg）加强力霉素和 emricasan 仅接受口服灌胃治疗，每天两次，在金黄色葡萄球菌注射后 4 小时开始，共 7 天。与安慰剂相比，所有三组，即安慰剂加强力霉素、emricasan 加强力霉素和 emricasan 治疗组，均表现出生物学效应，病变大小均减小（*p=0.0277，****p<0.0001，****p<0.0001），细菌负荷也减少（***p=0.003，****p<0.0001，****p<0.0001）。重要的是，emricasan 对金黄色葡萄球菌的疗效不是由于直接的抗菌活性。总之，泛半胱天冬酶抑制剂 emricasan 和 emricasan 加强力霉素减少了体内的病变大小和细菌负荷，并且 emricasan 是一种针对 MRSA 皮肤感染的潜在宿主定向免疫疗法在临床前小鼠模型中。
