Antimicrobials and Drug Resistance
Many pathogenic microbes have developed resistance to current antibiotics with devastating societal, economic and human health impacts. Microbial drug resistance significantly increases the length of hospitalization, complicates the treatment of other conditions, may require the use of more toxic alternative treatments and can leave no therapeutic options. The threat posed by methicillin resistant Staphylococcus aureus (MRSA) and other multiple drug resistant (MDR) human pathogens, has spurred the USA federal government to consider tax incentives, extended patent protection and a streamlined FDA approval process to invigorate the development of new antibiotics. As a result, pharmaceutical companies are taking a second look at new antibacterial compounds including those developed at research universities. At UMass the Riley lab is developing novel antimicrobials based upon the bacteriocin protein family, which are proteins produced by bacteria of one strain and active against bacteria of a closely related strain. The bacteriocin family of proteins is diverse in size, microbial targets, and modes of action. Anti-microbial proteins in this family show high potency, high target specificity, cover a vast range of pathogens, kill without co-lateral damage to the microbiome or to host cells, can penetrate biofilms and have high stability/durability. These properties, and ease of large-scale production, make a compelling case for targeted biomedical exploitation of the bacteriocins. The Wang lab studies a second family of antimicrobial peptides called NCR peptides, which a legume deploys on its associated bacterium, Sinohrizobium meliloti. S. meliloti shares ancestry and invasion strategies with a group of animal pathogens responsible for chronic infections. NCR peptides block the division of bacteria and compromise their cell membrane, leading to lethality at high doses. They comprise a large (>600 members per genome) and diverse family, with certain members displaying broad-spectrum antimicrobial activities. The NCR family offers a rich resource of antimicrobials relevant to human health and crop protection. The Wang lab is collaborating with the Baldwin lab to assess the efficacy of NCR peptides on the human pathogen Brucella abortus. The Telfer lab has shown the antibacterial activity of WC1 SRCR domains against multiple serovars and species of Leptospira and is evaluating their activity against other pathogens such as Borrelia and Mycobacteria. The Chien lab studies how energy-dependent proteases dynamically sculpt the proteome during bacterial growth and development. Because protein degradation is required in many human pathogens for full virulence, these proteases represents a new class of antibiotic susceptible targets that are currently underexplored. A different approach has been taken by the Klingbeil lab to identify trypanocidal compounds. Trypanosomes are protozoans and like other eukaryotic cells challenging to kill using antibiotics. Although trypanocidal chemotherapeutic agents are available, they produce toxic side effects and drug resistance is a concern. The Klingbeil Lab studies novel aspects of nuclear and mitochondrial DNA replication in Trypanosoma brucei to develop more selective therapies to treat African sleeping sickness. The Klingbeil lab is also collaborating with Sergey Savinov and the Small Molecule Screening Facility to establish high throughput screens for the identification of new classes of anti-trypanosomal compounds. Of particular interest are extracts prepared from the plant cell library recently donated from Monsanto. The Schiffman lab synthesizes new materials from natural polymers and plant-derived agents because they offer us a platform of intrinsic properties. Some of the intrinsic properties include, antimicrobial, biocidal, anti-insecticidal, and quorum sensing. The Schiffman lab focuses on being able to deliver these compounds in a way that enhances these intrinsic properties.