Office: ISA 6204
Lab: ISA 6014
B.S. (hons) Microbiology, University of East Anglia (England)
Ph.D. Molecular Microbiology, University of Sheffield (England)
Postdoctoral Fellow, University of Georgia
Research Assistant Professor, University of Missouri-Columbia
- Molecular mechanisms of disease causation in Methicillin Resistant Staphylococcus aureus (MRSA)
- Antibacterial Drug Discovery Targeting the ESKAPE Pathogens
Molecular mechanisms of disease causation in Methicillin Resistant Staphylococcus aureus (MRSA): Staphylococcus aureus is a highly virulent and widely successful human pathogen, which is speculated to be the most common cause of infectious disease and death in the United States. S. aureus is almost entirely unique amongst bacterial pathogens, as it can cause infection in almost every ecological niche of the human host. These range from the relatively benign, such as skin and soft tissue infections, boils, cellulitis and abscesses; to the systemic and life-threatening, such as endocarditis, septic arthritis, osteomyelitis, pneumonia and septicemia. Historically, S. aureus infections were confined to healthcare settings, afflicting the immunocompromised. Recently, however, there has been a meteoric increase of severe invasive disease in healthy subjects lacking any predisposing factors. This trendshift is the result of, hypervirulent strains of MRSA that have evolved in the community (CA-MRSA). Of concern, these CA-MRSA strains appear to be displacing existing hospital-associated MRSA isolates in clinical settings. The significance of this is further compounded by wide-spread antibiotic resistance in S. aureus, and the emergence of isolates resistant to last resort antibiotics. Thus the search for novel antimicrobial targets is crucial in our fight against a return to the pre-antibiotic era, where invasive S. aureus infections carried mortality rates of up to 90%.
In the Shaw lab, we use molecular tools to investigate the mechanisms of diseases causation by this highly successful bacterium. These broadly proceed along two distinct lines: The first is an analysis of regulatory elements, and how they coordinate and modulate the progression of infection. This includes the study of sigma factors, two-component systems and DNA-binding proteins, and their influence on physiological and pathogenic processes. We use next-generation sequencing tools, biochemical analyses and ex vivo/in vivo models of infection to understand gene targets of these regulatory elements, and their downstream effects of bacterial behavior and infectious capacity. Our second focus is centered on proteases, and their involvement in the virulence process. Typically ~2% of all genomes are dedicated to encoding proteases. In S. aureus, that number is closer to 5%, suggesting an overrepresentation in this organism. From work in our laboratory we have shown that a large number of proteolytic enzymes, be they secreted, or located in the membrane and/or cytoplasm, are key players in the virulence process. As such, we work to understand exactly how these enzymes define the infectious behavior of S. aureus, and to identify their specific protein substrates.
Antibacterial Drug Discovery Targeting the ESKAPE Pathogens: Despite the success of antimicrobial therapeutics in the past 70 years, infectious diseases remain the second-leading cause of mortality worldwide, causing 17 million deaths annually. Of this, the overwhelming majority are the result of bacterial pathogens. In the United States, there are almost 2 million hospital acquired infections each year, resulting in approximately 100,000 deaths. Perhaps the most significant public health concern in the context of bacterial infectious disease is the continued and rapid emergence of drug resistant strains during antibiotic treatment. Many bacteria are now unresponsive to conventional therapeutics, whilst still causing community and hospital acquired infections worldwide, leading to life-threatening and lethal diseases. Recently, the World Health Organization identified antimicrobial resistance as one of the three greatest threats facing mankind in the 21st century. As such, there is an undeniable and desperate need to develop new antibacterial therapeutics to fight the infections caused by these virtually untreatable pathogens. Unfortunately, the pace of drug resistance has outstripped the discovery of new antimicrobial agents, creating an urgent need for new antibiotics with novel mechanisms of action. The question is how we approach this, given that only 4 new classes of antibiotics have been marketed since 1970, and only 6 new antibiotics were approved by the FDA between 2003 and 2010. Indeed, there was a 75% decline in FDA approval for antibacterial agents from 1983-2007, largely the result of declining drug discovery efforts in industry. The is made even more concerning by the fact that only 4-5 companies are now seriously working on antimicrobial therapeutic development in the marketplace.
As such, in the Shaw lab, we work with a number of chemists and other research groups on the USF campus to identify new antimicrobial agents. These efforts are primarily focused on the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter cloacae). These are bacterial species that the CDC estimates cause more than two-thirds of all hospital-associated infections in the United States. They were identified by the Infectious Disease Society of America as causing the majority of infections in US hospitals, and having effectively managed to escape the activity of existing antimicrobial agents. Our work runs the entire spectrum of drug discovery, from hit identification, to lead development, in vivo efficacy testing, assessing anti-biofilm activity and mechanism of action studies.
Jessie Adams, Kirsten Antonen, Leila Casella, Renee Fleeman, Brittney Gimza, Cody Johnson, Brooke Nemec, Hailey Schuckel, Rahmy Tawfik, Andy Weiss