Citations 3
A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections
Blaskovich, Mark A. T. , Hansford, Karl A. , Butler, Mark S. , Ramu, Soumya , Kavanagh, Angela M. , Prasetyoputri, Anggia , Pitt, Miranda E. , Huang, Johnny X. , Lindahl, Fredrik, Ziora, Zyta M. , Bradford, Tanya A. , Muldoon, Craig, Premraj, Rajaratnam , Pelingon, Ruby , Edwards, David J. , Amado, Maite , Woischnig, Anne-Kathrin , Breidenstein, Elena B. M. , Stincone, Anna, Karau, Melissa J. , Greenwood‐Quaintance, Kerryl E. , Wootton, Mandy , James, Meagan L. , Hutton, M. , Mahdi, Layla K. , Trott, Darren J. , Wu, Xiaoqian, Niles, Samantha , Lewis, Kim , Yim, Juwon , Rice, Seth, Rybak, Michael J. , Ishmael, Chad R. , Hori, Kellyn R. , Francis, Kevin P. , Jarrad, Angie M , Prasetyoputri, Anggia , Pitt, Miranda E , Huang, Johnny X , Ziora, Zyta M , Bradford, Tanya , Rajaratnam, Premraj , Pelingon, Ruby , Zhang, Bing , Elliott, Alysha G , Zuegg, Johannes , Coin, Lachlan , Khanna, Nina , Stincone, Anna , Mason, Clive , Cho, Hye-Kyung , Karau, Melissa , Greenwood-Quaintance, Kerryl , Patel, Robin , Wootton, Mandy , James, Meagan L , Hutton, Melanie L , Lyras, Dena , Ogunniyi, Abiodun D , Mahdi, Layla K , Niles, Samantha , Lewis, Kim , Smith, Jordan R , Barber, Katie E , Rybak, Michael J , Ishmael, Chad R , Hori, Kellyn R , Bernthal, Nicholas M , Francis, Kevin P , Paterson, David L. , Cooper, Matthew A , Blaskovich, Mark A T , Edwards, David J., Khan, Nawaz, Patel, Robin , Roberts, Jason A
Science Translational Medicine | September 14, 2022 | Volume: 14 | Issue: 662 | Pages: No page available
Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria ( Staphylococcus aureus and Streptococcus pneumoniae ) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC 90 ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae , as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.
Enterococcus faecalis readily colonizes the entire gastrointestinal tract and forms biofilms in a germ-free mouse model
Barnes, Aaron M. T. , Dale, Jennifer L. , Chen, Yuqing , Manias, Dawn A., Quaintance, Kerryl E. Greenwood, Karau, Melissa K., Kashyap, Purna , Patel, Robin , Wells, Carol L., Dunny, Gary M. , Greenwood Quaintance, Kerryl E, Karau, Melissa , Patel, Robin
Virulence | August 25, 2016 | Volume: 8 | Issue: 3 | Pages: 282-296
The Impact ofStaphylococcus aureus-Associated Molecular Patterns on Staphylococcal Superantigen-Induced Toxic Shock Syndrome and Pneumonia
Tilahun, Ashenafi Y. , Karau, Melissa J. , Ballard, Alessandro D. , Gunaratna, Miluka P. , Thapa, Anusa , David, Chella S., Patel, Robin , Rajagopalan, Govindarajan , Karau, Melissa , Ballard, Alessandro , Patel, Robin
Mediators of Inflammation | June 12, 2014 | Volume: 2014 | Issue: No issue available | Pages: 1-13
Staphylococcus aureusis capable of causing a spectrum of human illnesses. During seriousS. aureusinfections, the staphylococcal pathogen-associated molecular patterns (PAMPs) such as peptidoglycan, lipoteichoic acid, and lipoproteins and even intactS. aureus, are believed to act in conjunction with the staphylococcal superantigens (SSAg) to activate the innate and adaptive immune system, respectively, and cause immunopathology. However, recent studies have shown that staphylococcal PAMPs could suppress inflammation by several mechanisms and protect from staphylococcal toxic shock syndrome, a life-threatening systemic disease caused by toxigenicS. aureus. Given the contradictory pro- and anti-inflammatory roles of staphylococcal PAMPs, we examined the effects ofS. aureus-derived molecular patterns on immune responses driven by SSAgin vivousing HLA-DR3 and HLA-DQ8 transgenic mice. Our study showed that neitherS. aureus-derived peptidoglycans (PGN), lipoteichoic acid (LTA), nor heat-killedStaphylococcus aureus(HKSA) inhibited SSAg-induced T cell proliferationin vitro. They failed to antagonize the immunostimulatory effects of SSAgin vivoas determined by their inability to attenuate systemic cytokine/chemokine response and reduce SSAg-induced T cell expansion. These staphylococcal PAMPs also failed to protect HLA-DR3 as well as HLA-DQ8 transgenic mice from either SSAg-induced toxic shock or pneumonia induced by a SSAg-producing strain ofS. aureus.