Publications by authors named "Kristen A Muñoz"

2 Publications

  • Page 1 of 1

Facilitating Compound Entry as a Means to Discover Antibiotics for Gram-Negative Bacteria.

Acc Chem Res 2021 Mar 26;54(6):1322-1333. Epub 2021 Feb 26.

Department of Chemistry Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, Illinois 61801, United States.

ConspectusIt has been over half a century since the last class of antibiotics active against the most problematic Gram-negative bacteria was approved by the Food and Drug Administration (FDA). The major challenge with developing antibiotics to treat these infections is not drug-target engagement but rather the inability of most small molecules to traverse the Gram-negative membranes, be retained, and accumulate within the cell. Despite an abundance of lead compounds, limited understanding of the physicochemical properties needed for compound accumulation (or avoidance of efflux) in Gram-negative bacteria has precluded a generalizable approach for developing Gram-negative antibiotics. Indeed, in many instances, despite years of intensive derivatization efforts and the synthesis of hundreds of compounds aimed at building in Gram-negative activity, little or no progress has been made in expanding the spectrum of activity for many Gram-positive-only antibiotics. In this Account, we describe the discovery and successful applications of a promising strategy for enhancing the accumulation of Gram-positive-only antibiotics as a means of imbuing compounds with broad-spectrum activity.Utilizing a prospective approach examining the accumulation in for more than 180 diverse compounds, we found that small molecules have an increased likelihood to accumulate in when they contain an ionizable itrogen, have low hree-dimensionality, and are igid. Implementing these guidelines, codified as the "eNTRy rules" and assisted by web application www.entry-way.org, we have facilitated compound entry and systematically built Gram-negative activity into Gram-positive-only antibiotics. Though each antibiotic will have case-specific considerations, we describe a set of important criteria to consider when selecting candidate Gram-positive-only antibiotics for conversion to Gram-negative-active versions via the eNTRy rules. As detailed herein, using this blueprint the spectrum of activity was expanded for three antibiotic classes that engage three different biological targets: DNA gyrase inhibitor 6DNM, FabI inhibitor Debio-1452, and FMN riboswitch inhibitor Ribocil C. In each scenario, the eNTRy rules guided the synthesis of key analogues predisposed to accumulate in Gram-negative bacteria leading to compounds that display antibiotic activity (minimum inhibitory concentrations (MIC) ≤8 μg mL) against and other Gram-negative ESKAPE pathogens. While the eNTRy rules will continue to be refined and enhanced as more accumulation data is gathered, on the basis of these collective results and on other examples not covered herein it is clear that the eNTRy rules are actionable for the development of novel broad-spectrum antibiotics from Gram-positive-only compounds. By enabling the prediction of compound accumulation, the eNTRy rules should facilitate the process of discovering and developing novel antibiotics active against Gram-negative bacteria.
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http://dx.doi.org/10.1021/acs.accounts.0c00895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969460PMC
March 2021

Configurable lipid membrane gradients quantify diffusion, phase separations and binding densities.

Soft Matter 2015 Nov;11(42):8217-20

Keck Science Department, Claremont, CA, USA. and Scripps College, Claremont, CA, USA.

Single-experiment analysis of phospholipid compositional gradients reveals diffusion coefficients, phase separation parameters, and binding densities as a function of localized lipid mixture. Compositional gradients are formed by directed self assembly where rapid-prototyping techniques (i.e., additive manufacturing or laser-cutting) prescribe lipid geometries that self-spread, heal and mix by diffusion.
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http://dx.doi.org/10.1039/c5sm02013aDOI Listing
November 2015