ANTIBACTERIAL DRUG DISCOVERY

For example, transcription is controlled in bacterial cells using DNA binding proteins, two-component regulatory systems, and by alternative components of ​the RNA Polymerase complex. Our group has published 
studies on each of these processes, defining how they
contribute to the manipulation of gene expression, 
​and the progression of disease.

The control of translation in bacteria is driven by
regulatory RNA molecules. These are encoded within
DNA like regular genes, but commonly do not specify 
a translatable product. Instead, they target other 
message bearing RNA molecules (mRNA) within the 
cell, and either stabilize or destabilize them. In this 
​way, they lead to discrete, specific, and wide ranging
effects on protein synthesis.

​In the context of proteins, these are often made in an inactive form, requiring modification or processing to resulting in biological function. Conversely, some proteins are synthesized in a functional state, but must be specifically and discretely deactivated at key moments during growth. In the Shaw lab, we work on all kinds of these post-translation modifications, with a specific focus on how proteolysis, the cleavage of proteins by proteases, maintains cellular homeostasis, and facilitates the infectious

process. Towards this latter point we have also developed cutting edge proteomic tools to study the impact of proteases on host-pathogen interaction. In so doing, we are shining important new light on exactly how bacteria use these vital enzymes to facilitate central processes such as nutrition, immune evasion, and movement to new sites of infection with the host.

THE REGULATION OF VIRULENCE IN MRSA

AT THE UNIVERSITY OF  SOUTH FLORIDA

GENOMIC EPIDEMIOLOGY OF S. aureus INFECTIONS

SHAW

                  lAB   

RESEARCH IN THE SHAW LAB

• ​The Regulation of Virulence in the Major Human Pathogen, Methicillin Resistant Staphylococcus aureus​ (MRSA)

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• ​Molecular Epidemiology of S. aureus Infections
  

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• Antibacterial Drug Discovery Targeting the ESKAPE Pathogens

Staphylococcus aureus is a highly virulent and widely successful human pathogen that is among 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 infections 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. 
The manner by which S. aureus achieves this is 
through the production of an arsenal of secreted 
and surface associated virulence factors. The 
production of each of these elements is tightly 
controlled at all tiers of the regulatory spectrum, 
allowing S. aureus to discretely titrate in or out 
the production of key virulence factors in a given
niche. This then allows for the selective and disease specific regulation of pathogenic behaviors and provides a basis for control of the broad swath of infections caused by this organism. As such, a major focus of our work is to understand the dynamics of S. aureus infection, exploring how virulence factors are controlled within the host to specifically bring about the myriad disease states caused by this dangerous pathogen.

Another major arm of our work is studying natural variability in the pathogenic potential of S. aureus clinical isolates. Historically, S. aureus infections were confined to healthcare settings, afflicting the immunocompromised. However, over the last few decades, there has been a meteoric increase of severe invasive disease in healthy subjects lacking any predisposing factors. This trend shift is the result of, hypervirulent strains of MRSA that have evolved in the community (CA-MRSA). Of concern, these CA-MRSA strains have moved into clinical setting displacing existing hospital-associated MRSA isolates. As such, we work with infectious diseases clinicians in the USF College of Medicine and at Tampa General Hospital (TGH) to study the natural variability of circulating S. aureus isolates in the Tampa Bay region. Here, we collect strains from TGH, subject them to genome sequencing at the USF Genomics Institute, and characterize their infectious properties in the lab. We then correlate patient outcomes with our phenogenomic characterization of bacterial strains to gain new insight into the features that influence S. aureus infections in humans. This work is part of a wider effort at USF through our newly founded Center for Antimicrobial Resistance, which Dr Shaw directs. 

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.

​As such, in the Shaw lab, we target our drug discovery efforts towards 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.

To this end, we have both natural productsas well as hit-to-lead optimization projects that we collaborate on withchemistry groups both here at USF as well as nationally at a wealth of other institutions​.