Nanomaterials in the Diagnosis and Treatment of Infectious Disease
The emergence of resistance to multiple antimicrobial agents in pathogenic bacteria has become a significant global public health threat. Drug-resistant bacterial infections cause considerable patient mortality and morbidity, and rising antibiotic resistance is seriously threatening the vast medical advancements made possible by antibiotics over the past 70 years. Without developing innovative approaches to combat these multi-drug resistant pathogens, many fields of medicine will be severely affected, including surgery, premature infant care, cancer chemotherapy, care of the critically ill, and transplantation medicine, all of which are feasible only with the existence of effective antibiotic therapy. This situation is so dire that the world health organization has identified multi-drug resistant (MDR) bacteria as one of the top three threats to human health.
Nanoscale antivirals and antibiotics. One-third of the global population (3 billion people) is estimated to be infected with M. tuberculosis (TB). A majority of those infected will never contract active TB and will remain asymptomatic. However, for immunocompromised patients TB is a major cause of death worldwide. For example, TB is the leading cause of death in HIV-positive patients. The World Health Organization estimates that 9 million people contracted active TB in 2006 (~6 million from Southeast Asia and Africa alone) and over 1 million died from the disease. Yet over 1.5 million people in India alone are believed to undergo useless TB tests each year, and both HIV and TB have become resistant to current treatments and can hide in "sanctuary sites" such as the brain, where small molecule drugs often have difficulty penetrating.
Our lab is addressing challenging problems in the diagnosis and treatment of infectious diseases such as HIV and TB. In developing new diagnostic methods and therapeutics, we seek to exploit many of the novel physical and chemical properties of nanoscale materials. A few examples are highlighted below.
Synthetic nanometer-scale systems have the potential to overcome many limitations of conventional small molecule therapeutic agents. For instance, small molecules typically have short blood circulation times (hrs), rely on a single high-affinity contact to a disease target, and are incapable of disrupting protein-protein interactions that often drive disease pathogenisis. In contrast, nanoscale systems can provide long circulation times (days to weeks), have tunable valency, and are adept at preventing protein-protein interactions. We have hypothesized that gold nanocrystals may possess a number of attributes that make them useful drug candidates. Gold nanocrystals are now accessible in a range of well defined sizes from ca. 1.0 nm to 10 nm. Gold nanocrystals also enable one to rapidly synthesize combinatorial libraries of nanoscale compounds; using organothiol exchange reactions, combinations of two or more chemically distinct ligands can be attached to a single particle to create multi-ligand and multi-functional systems. The ability to rapidly assemble mixed thiol monolayers on a nanoscale platform provides a powerful tool that can be used to tune particle binding affinity to a disease target, and control cellular internalization and sub-cellular localization.
The potential benefits of gold nanocrystal therapeutics were demonstrated in our lab with the synthesis of a multivalent gold conjugate that effectively inhibited HIV entry in T-cells (see model below).
Model of a 2.0 nm diameter gold nanocrystal therapeutic that effectively inhibits HIV entry into human T cells.
We have also developed a new method for generating libraries of mixed thiol monolayer/gold nanoparticle conjugates that may be screened for antibiotic activity. In this “small molecule variable ligand display” (SMVLD) approach, mixtures of thiol ligands (typically three or more) are combined with p-mercaptobenzoic acid (pMBA)-modified gold nanoparticles in one pot to create mixed ligand monolayer/gold nanoparticle conjugates that are rapidly isolated via simple precipitation for subsequent biological screening purposes. Our gold nanoparticle library has yielded conjugates that are highly active in vitro toward the growth inhibition of TB, multi-drug resistant E. coli, and multi-drug resistant K. pneumoniae. Moreover, we have discovered that E. coli does not develop signficant resistance to our gold nanoparticle antibiotics. Current work in the lab is focused on understanding nanoscale structure-activity relationships (NSAR) and targets of these novel antibiotics.