Antibacterial drug discovery targeting the ESKAPE pathogens
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. However, over the last
decade or so, 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 appear to be displacing existing hospital-associated MRSA isolates in clinical settings. Coupled with the fact that numerous attempts to make a S. aureus vaccine have failed over the last 10+ years, and that antibiotic resistance is widespread and endemic, we are presented with the very serious prospect of a post antibiotic era, and a return to simple infections once again being life threatening. Invasive S. aureus infections, for example, carry mortality rates up to 90% without therapeutic intervention.
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.
We have both natural products discovery based projects (with the lab of Dr Bill Baker in the Department of Chemistry, here at USF, and the lab of Dr Leslie Hicks at UNC-Chapel Hill), as well as hit-to-lead optimization studies with synthetic medicinal chemists, both here at USF (the laboratories of Dr Ed Turos and Dr Jim Leahy, USF Chemistry), as well as at other institutions (Dr Roman Manetsch, Northeastern University; Torrey Pines Institute for Molecular Sciences, Port St Lucie, FL).
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
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 largely drive 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 Shaw lab, we
have our own Next-Generation Sequencer: an Ion
Torrent Personal Genome Machine (PGM). We
have used this to perform a wealth of RNAseq
analyses, identifying myriad of novel regulatory
RNAs in the S. aureus cell.
As such, in the Shaw lab, we use molecular tools to investigate the mechanisms used by S. aureus to cause human disease. To do this, we focus on regulatory processes, at all levels, within the bacterial cell. In modern molecular
biology central dogma is the flow of information from
DNA ⇒ RNA ⇒ Protein. Each of these processes is
discretely controlled, by a wealth of mechanisms,
so as to conserve cellular resources, and facilitate
expedient adaption to the environment. In the
Shaw lab, we study how these process are
controlled in MRSA.