Efficacy of Intranasal Administration of the Recombinant Endolysin SAL200 in a Lethal Murine Staphylococcus aureus Pneumonia Model

Abstract

SAL200 is derived from a phage endolysin and is a novel candidate drug for the treatment of Staphylococcus aureus infection. We investigated the efficacy of the recombinant endolysin SAL200 in a lethal murine pneumonia model. Lethal pneumonia was established by intranasally administering a methicillin-susceptible (Newman) or methicillin-resistant (LAC) S. aureus strain into BALB/c mice. The mice were treated with a single intranasal administration of SAL200 or phosphate-buffered saline at 2 h after S. aureus infection. The survival rates were recorded until 60 h after the bacterial challenge. The bacterial loads in the lungs and blood, histopathology of lung tissues, and serum cytokine levels were evaluated following the S. aureus challenge. The SAL200-treated group and control group exhibited 90% to 95% and 10% to 40% survival rates, respectively. The bacterial loads in the lungs of the SAL200-treated group were significantly lower by ∼10-fold than those of the control group as early as 1 h after treatment. Histopathologic recovery of pneumonia was observed in the SAL200-treated mice. The cytokine levels were comparable between groups. These results suggest that direct administration of SAL200 into the lungs could be a potential adjunct treatment against severe pneumonia caused by S. aureus.

Pharmacokinetics and pharmacodynamics in the treatment of cutaneous leishmaniasis – challenges and opportunities

“…When administered orally, DNDI-0690 was able to effectively clear all parasites from the skin. 32 Another example was observed when evaluating the efficacy of benzoxaborole compounds LSH001 and LSH003 in the same model; topical application of LSH003 was unable to reduce the lesion size progression (and parasite load) whereas oral administration of the drug reduced this load by 50%. The opposite effect was seen for LSH001, which halted lesion size progression upon topical administration whilst lacking activity upon oral administration.…”

“…The experiment aimed to answer three questions: (i) does DNDI-0690 distribute to the skin, (ii) which administration route, topical or oral, is most suitable and, (iii) does pathology impact skin drug distribution. 32 Skin microdialysis and Franz diffusion cell studies revealed that DNDI-0690 permeated poorly into healthy and diseased skin upon topical application of a saturated solution. An oral dose of 50 mg kg −1 instead lead to rapid distribution of protein unbound DNDI-0690 from the blood into the infected dermis as indicated by a ratio of the area under the curve (0 to 6 hours) of free DNDI-0690 in the skin to that in the blood greater than 80%.…”

Efficacy of Phage- and Bacteriocin-Based Therapies in Combatting Nosocomial MRSA Infections

“…The ability of SAL200 to treat MRSA-associated pneumonia in a mouse model has been investigated. The endolysin rescued 95-100% of mice following infection, whereas 40-93% of the control group died following 60 h of infection ( Bae et al, 2019 ). Aquaphor gel was used to incorporate the lysin LysGH15 and apigenin, forming a LysGH15-api-Aquaphor ointment ( Cheng et al, 2018 ).…”

Exploring Virulence Factors and Alternative Therapies against Staphylococcus aureus Pneumonia

“…The survival rate further increased to 100% when LysGH15 was combined with apigenin, a naturally occurring flavonoid [ 222 ]. In a second study, conducted in 2018, phage-derived endolysin SAL200 was tested in murine SAP, and achieved higher survival, lower bacterial burden, and improved lung histopathology compared to the control group [ 223 ].…”