One of the major problems in the health care industry is multi-drug resistant infections. Secondary infections of drug-resistant bacteria such as S. aureus in hospitals, and the multidrug resistant forms of M. tuberculosis, have become global health problems.
The aim of this proposal is to isolate potential broad-spectrum antibiotic agents that could revolutionize how we treat common and multi-drug-resistant bacterial infections, and possibly even victims of bio-terrorism. We previously found that small structural changes can cause large- pore bacterial mechanosensitive channels to mis-gate, severely compromising the growth and viability of the bacterial cell. There are many features that make these channels ideal candidates for pharmacological targets. The channels are: (1) expressed in all phases of bacterial growth, suggesting that agonists would attack even microbes that have a tendency to remain dormant for long periods of time, such as M. tuberculosis. (2) found in essentially every bacterial species, but are unique to microbes;no family members are found in any mammal. (3) highly conserved, so drugs are likely be broad spectrum. (4) Finally, we have numerous tools for the project including null strains, expression constructs, and the approval for the use of the High Throughput Screening (HTS) facility on campus. In sum, the aim of this proposal is to develop the assay, and screen the 200,000 compounds in the HTS library to isolate compounds that are potential antibiotic drugs that target mechanosensitive channels.
We propose to isolate a new generation of antibiotics that would be ideal for treating multi-drug resistant and otherwise difficult to treat infections. The antibiotics isolated could also have implications in emergency situations including treating victims of acts of bioterrorism.
| Iscla, Irene; Wray, Robin; Wei, Shuguang et al. (2014) Streptomycin potency is dependent on MscL channel expression. Nat Commun 5:4891 |
| Yang, Li-Min; Zhong, Dalian; Blount, Paul (2013) Chimeras reveal a single lipid-interface residue that controls MscL channel kinetics as well as mechanosensitivity. Cell Rep 3:520-7 |
| Iscla, Irene; Wray, Robin; Blount, Paul (2012) The dynamics of protein-protein interactions between domains of MscL at the cytoplasmic-lipid interface. Channels (Austin) 6:255-61 |
| Booth, Ian R; Blount, Paul (2012) The MscS and MscL families of mechanosensitive channels act as microbial emergency release valves. J Bacteriol 194:4802-9 |
| Iscla, Irene; Blount, Paul (2012) Sensing and responding to membrane tension: the bacterial MscL channel as a model system. Biophys J 103:169-74 |
