@article{garcia_blackledge_michalek_su_ptacek_eipers_morrow_lefkowitz_melander_wu_2017, title={Targeting of Streptococcus mutans Biofilms by a Novel Small Molecule Prevents Dental Caries and Preserves the Oral Microbiome}, volume={96}, ISSN={["1544-0591"]}, DOI={10.1177/0022034517698096}, abstractNote={Dental caries is a costly and prevalent disease characterized by the demineralization of the tooth’s enamel. Disease outcome is influenced by host factors, dietary intake, cariogenic bacteria, and other microbes. The cariogenic bacterial species Streptococcus mutans metabolizes sucrose to initiate biofilm formation on the tooth surface and consequently produces lactic acid to degrade the tooth’s enamel. Persistence of S. mutans biofilms in the oral cavity can lead to tooth decay. To date, no anticaries therapies that specifically target S. mutans biofilms but do not disturb the overall oral microbiome are available. We screened a library of 2-aminoimidazole antibiofilm compounds with a biofilm dispersion assay and identified a small molecule that specifically targets S. mutans biofilms. At 5 µM, the small molecule annotated 3F1 dispersed 50% of the established S. mutans biofilm but did not disperse biofilms formed by the commensal species Streptococcus sanguinis or Streptococcus gordonii. 3F1 dispersed S. mutans biofilms independently of biofilm-related factors such as antigen I/II and glucosyltransferases. 3F1 treatment effectively prevented dental caries by controlling S. mutans in a rat caries model without perturbing the oral microbiota. Our study demonstrates that selective targeting of S. mutans biofilms by 3F1 was able to effectively reduce dental caries in vivo without affecting the overall oral microbiota shaped by the intake of dietary sugars, suggesting that the pathogenic biofilm-specific treatment is a viable strategy for disease prevention.}, number={7}, journal={JOURNAL OF DENTAL RESEARCH}, author={Garcia, S. S. and Blackledge, M. S. and Michalek, S. and Su, L. and Ptacek, T. and Eipers, P. and Morrow, C. and Lefkowitz, E. J. and Melander, C. and Wu, H.}, year={2017}, month={Jul}, pages={807–814} }
 @article{stowe_thompson_peng_su_blackledge_draughn_coe_johannes_lapham_mackenzie_et al._2015, title={Membrane-Permeabilizing Activity of Reverse-Amide 2-Aminoimidazole Antibiofilm Agents Against Acinetobacter baumannii}, volume={12}, ISSN={["1875-5704"]}, DOI={10.2174/1567201811666140924125740}, abstractNote={Acinetobacter baumannii has quickly become one of the most insidious and prevalent nosocomial infections. Recently, the reverse-amide class of 2-aminoimidazole compounds (RA-2AI) was found both to prevent A. baumannii biofilm formation and also to disperse preexisting formations, putatively through interactions with cytosolic response regulators. Here we focus on how this class of antibiofilm agent traverses cellular membranes. Following the discovery of dosage-dependent growth rate changes, the cellular effects of RA-2AI were investigated using a combination of molecular assays and microscopic techniques. It was found that RA-2AI exposure has measureable effects on the bacterial membranes, resulting in a period of increased permeability and visible structural aberrations. Based on these results, we propose a model that describes how the structure of RA-2AI allows it to insert itself into and disrupt the fluidity of the membrane, creating an opportunity for increased molecular permeability.}, number={2}, journal={CURRENT DRUG DELIVERY}, author={Stowe, Sean D. and Thompson, Richele J. and Peng, Lingling and Su, Zhaoming and Blackledge, Meghan S. and Draughn, G. Logan and Coe, William H. and Johannes, Eva and Lapham, Valerie K. and Mackenzie, John and et al.}, year={2015}, pages={223–230} }
 @article{blackledge_worthington_melander_2013, title={Biologically inspired strategies for combating bacterial biofilms}, volume={13}, ISSN={["1471-4973"]}, DOI={10.1016/j.coph.2013.07.004}, abstractNote={Infections caused by bacterial biofilms are a significant global health problem, causing considerable patient morbidity and mortality and contributing to the economic burden of infectious disease. This review describes diverse strategies to combat bacterial biofilms, focusing firstly on small molecule interference with bacterial communication and signaling pathways, including quorum sensing and two-component signal transduction systems. Secondly we discuss enzymatic approaches to the degradation of extracellular matrix components to effect biofilm dispersal. Both of these approaches are based upon non-microbicidal mechanisms of action, and thereby do not place a direct evolutionary pressure on the bacteria to develop resistance. Such approaches have the potential to, in combination with conventional antibiotics, play an important role in the eradication of biofilm based bacterial infections.}, number={5}, journal={CURRENT OPINION IN PHARMACOLOGY}, author={Blackledge, Meghan S. and Worthington, Roberta J. and Melander, Christian}, year={2013}, month={Oct}, pages={699–706} }
 @article{blackledge_melander_2013, title={Programmable DNA-binding small molecules}, volume={21}, ISSN={["0968-0896"]}, DOI={10.1016/j.bmc.2013.04.023}, abstractNote={Aberrant gene expression is responsible for a myriad of human diseases from infectious diseases to cancer. Precise regulation of these genes via specific interactions with the DNA double helix could pave the way for novel therapeutics. Pyrrole-imidazole polyamides are small molecules capable of binding to pre-determined DNA sequences up to 16 base pairs with affinity and specificity comparable to natural transcription factors. In the three decades since their development, great strides have been made relating to synthetic accessibility and improved sequence specificity and binding affinity. This perspective presents a brief history of early seminal developments in the field and highlights recent reports of the utility of polyamides as both genetic modulators and molecular probes.}, number={20}, journal={BIOORGANIC & MEDICINAL CHEMISTRY}, author={Blackledge, Meghan S. and Melander, Christian}, year={2013}, month={Oct}, pages={6101–6114} }
 @misc{worthington_blackledge_melander_2013, title={Small-molecule inhibition of bacterial two-component systems to combat antibiotic resistance and virulence}, volume={5}, ISSN={["1756-8927"]}, DOI={10.4155/fmc.13.58}, abstractNote={ Infections caused by multidrug-resistant bacteria are a considerable and increasing global problem. The development of new antibiotics is not keeping pace with the rapid evolution of resistance to almost all clinically available drugs, and novel strategies are required to fight bacterial infections. One such strategy is the control of pathogenic behaviors, as opposed to simply killing bacteria. Bacterial two-component system (TCS) signal transduction pathways control many pathogenic bacterial behaviors, such as virulence, biofilm formation and antibiotic resistance and are, therefore, an attractive target for the development of new drugs. This review presents an overview of TCS that are potential targets for such a strategy, describes small-molecules inhibitors of TCS identified to date and discusses assays for the identification of novel inhibitors. The future perspective for the identification and use of inhibitors of TCS to potentially provide new therapeutic options for the treatment of drug-resistant bacterial infections is discussed. }, number={11}, journal={FUTURE MEDICINAL CHEMISTRY}, author={Worthington, Roberta J. and Blackledge, Meghan S. and Melander, Christian}, year={2013}, month={Jul}, pages={1265–1284} }