TY - JOUR
T1 - Liposomal mupirocin holds promise for systemic treatment of invasive Staphylococcus aureus infections
AU - Goldmann, Oliver
AU - Cern, Ahuva
AU - Muesken, Mathias
AU - Rohde, Manfred
AU - Weiss, William
AU - Barenholz, Yechezkel
AU - Medina, Eva
N1 - Funding Information:
This work was supported in part by internal funding provided by the Helmholtz Centre for Infection Research to OG and EM and in part by the Barenholz Fund (AC and YB). The Barenholz fund was established by the Hebrew University of Jerusalem with a portion of YB Royalties from his Doxil royalties to support research activities in the Barenholz Lab. The neutropenic mouse lung infection model was supported by the National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services, under contract HHSN272201700084C. Dr. Ann Eakin from the NIAID is acknowledged for her help with this study.
Funding Information:
This work was supported in part by internal funding provided by the Helmholtz Centre for Infection Research to OG and EM and in part by the Barenholz Fund (AC and YB). The Barenholz fund was established by the Hebrew University of Jerusalem with a portion of YB Royalties from his Doxil royalties to support research activities in the Barenholz Lab. The neutropenic mouse lung infection model was supported by the National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health , Department of Health and Human Services , under contract HHSN272201700084C . Dr. Ann Eakin from the NIAID is acknowledged for her help with this study.
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/12/28
Y1 - 2019/12/28
N2 - Staphylococcus aureus is a major cause of severe invasive infections. The increasing incidence of infections caused by antibiotic-resistant strains such as methicillin-resistant S. aureus (MRSA), calls for exploration of new approaches to treat these infections. Mupirocin is an antibiotic with a unique mode of action that is active against MRSA, but its clinical use is restricted to topical administration because of its limited plasma stability and rapid degradation to inactive metabolites. Mupirocin was identified by a machine learning approach to be suitable for nano-liposome encapsulation. The computational predictions were verified experimentally and PEGylated nano-liposomal formulation of mupirocin (Nano-mupirocin) was developed. The aim of this study was to investigate the efficacy of this formulation when administered parenterally for the treatment of S. aureus invasive infections. Nano-mupirocin exhibited prolonged half-life of active antibiotic and displayed superior antimicrobial activity against S. aureus than free mupirocin in the presence of plasma. Parenteral application of Nano-mupirocin in a murine model of S. aureus bloodstream infection resulted in improved antibiotic distribution to infected organs and in a superior therapeutic efficacy than the free drug. Parenterally administered Nano-mupirocin was also more active against MRSA than free mupirocin in a neutropenic murine lung infection model. In addition, Nano-mupirocin was very efficiently taken up by S. aureus-infected macrophages via phagocytosis leading to enhanced delivery of mupirocin in the intracellular niche and to a more efficient elimination of intracellular staphylococci. The outcome of this study highlights the potential of Nano-mupirocin for the treatment of invasive MRSA infections and support the further clinical development of this effective therapeutic approach.
AB - Staphylococcus aureus is a major cause of severe invasive infections. The increasing incidence of infections caused by antibiotic-resistant strains such as methicillin-resistant S. aureus (MRSA), calls for exploration of new approaches to treat these infections. Mupirocin is an antibiotic with a unique mode of action that is active against MRSA, but its clinical use is restricted to topical administration because of its limited plasma stability and rapid degradation to inactive metabolites. Mupirocin was identified by a machine learning approach to be suitable for nano-liposome encapsulation. The computational predictions were verified experimentally and PEGylated nano-liposomal formulation of mupirocin (Nano-mupirocin) was developed. The aim of this study was to investigate the efficacy of this formulation when administered parenterally for the treatment of S. aureus invasive infections. Nano-mupirocin exhibited prolonged half-life of active antibiotic and displayed superior antimicrobial activity against S. aureus than free mupirocin in the presence of plasma. Parenteral application of Nano-mupirocin in a murine model of S. aureus bloodstream infection resulted in improved antibiotic distribution to infected organs and in a superior therapeutic efficacy than the free drug. Parenterally administered Nano-mupirocin was also more active against MRSA than free mupirocin in a neutropenic murine lung infection model. In addition, Nano-mupirocin was very efficiently taken up by S. aureus-infected macrophages via phagocytosis leading to enhanced delivery of mupirocin in the intracellular niche and to a more efficient elimination of intracellular staphylococci. The outcome of this study highlights the potential of Nano-mupirocin for the treatment of invasive MRSA infections and support the further clinical development of this effective therapeutic approach.
KW - Invasive infections
KW - Mupirocin
KW - Nano-mupirocin
KW - Nanoliposomes
KW - Parenteral administration
KW - Staphylococcus aureus
UR - http://www.scopus.com/inward/record.url?scp=85074756241&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2019.11.007
DO - 10.1016/j.jconrel.2019.11.007
M3 - Article
C2 - 31715276
AN - SCOPUS:85074756241
SN - 0168-3659
VL - 316
SP - 292
EP - 301
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -