Medicinal Chemistry Reviews

Volume 52, Chapter 17

Recent Advances Towards Rational Antibacterial Discovery:  Addressing Permeation and Efflux

Quentin P. Avila, Helen I. Zgurskaya, and Adam S. Duerfeldt

1.          Introduction                                                                                                               319

2.         New Mindsets In Antibacterial Development                                                        321

            2.1        Disparate Membrane Polarity in Gram-Negatives                         321

            2.2       Chemical Space and Structural Uniqueness of Gram-Negative

Actives                                                                                                            322

            2.3       Enhanced Antibacterial Potency                                                                 322

            2.4       Early Consideration of Combinatorial Therapy                                         322

            2.5       Development of Narrow-Spectrum Therapeutics                           323

            2.6       Non-Traditional Approaches to Antibacterial Development                    323

3.         Methods to Evaluate Antibacterial Activity                                                            323

            3.1        Chemical Modification of Cells                                                                    324

            3.2       Genetic Modification of Cells                                                                       325

4.         Methods to Determine Compound Permeation and Accumulation                    325

            4.1        Mass Spectrometry                                                                                       326

            4.2       Fluorescence                                                                                      326

            4.3       Electrophysiology and Liposome Swelling Assays                                    326

5.         Recent Examples of Rational Approaches to Enhance

Gram-Negative Accumulation                                                                                   328

            5.1        Sulfamoyladenosines                                                                                   329

            5.2       Oxazolidinones                                                                                             330

            5.3       Tetrahydropyran-Based Topoisomerase Inhibitors                                   332

            5.4       Diverse Chemotype Analysis                                                                       333

6.         Conclusion                                                                                                                 334

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