Antibacterial Drug Discovery: Some Assembly Required

ACS Infectious Diseases

Volumn 4, Issue 5, 2018, Pages 686-695

  Tommasi, Rubén ^a   Iyer, Ramkumar ^a   Miller, Alita A ^a  

^a Entasis Therapeutics   (United States)

Author keywords

accumulation; drug discovery; efflux; novel antibacterials; permeation; rules of uptake

Indexed keywords

ANTIINFECTIVE AGENT;

DRUG SCREENING; DRUG UPTAKE; GRAM NEGATIVE BACTERIUM; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; REVIEW; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG DEVELOPMENT; DRUG EFFECT; HIGH THROUGHPUT SCREENING; HUMAN; MICROBIAL SENSITIVITY TEST; PERMEABILITY; STRUCTURE ACTIVITY RELATION;

ANTI-BACTERIAL AGENTS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; GRAM-NEGATIVE BACTERIA; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; MICROBIAL SENSITIVITY TESTS; MOLECULAR STRUCTURE; PERMEABILITY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 85046904290     PISSN: None     EISSN: 23738227     Source Type: Journal    
DOI: 10.1021/acsinfecdis.8b00027     Document Type: Review

References (77)

1. Outterson, K., Rex, J. H., Jinks, T., Jackson, P., Hallinan, J., Karp, S., Hung, D. T., Franceschi, F., Merkeley, T., Houchens, C., Dixon, D. M., Kurilla, M. G., Aurigemma, R., and Larsen, J. (2016) Accelerating global innovation to address antibacterial resistance: introducing CARB-X. Nat. Rev. Drug Discovery 15, 589-590, 10.1038/nrd.2016.155
2. Rex, J. H., Talbot, G. H., Goldberger, M. J., Eisenstein, B. I., Echols, R. M., Tomayko, J. F., Dudley, M. N., and Dane, A. (2017) Progress in the Fight Against Multidrug-Resistant Bacteria 2005-2016: Modern Noninferiority Trial Designs Enable Antibiotic Development in Advance of Epidemic Bacterial Resistance. Clin. Infect. Dis. 65 (1), 141-146, 10.1093/cid/cix246
3. Årdal, C., Baraldi, E., Ciabuschi, F., Outterson, K., Rex, J. H., Piddock, L. J. V., and Findlay, D. (2017) To the G20: incentivising antibacterial research and development. Lancet Infect. Dis. 17 (8), 799-801, 10.1016/S1473-3099(17)30404-8
4. Towse, A., Hoyle, C. K., Goodall, J., Hirsch, M., Mestre-Ferrandiz, J., and Rex, J. H. (2017) Time for a change in how new antibiotics are reimbursed: Development of an insurance framework for funding new antibiotics based on a policy of risk mitigation. Health Policy 121 (10), 1025-1030, 10.1016/j.healthpol.2017.07.011
5. Rex, J. H., Goldberger, M., Eisenstein, B. I., and Harney, C. (2014) The evolution of the regulatory framework for antibacterial agents. Ann. N. Y. Acad. Sci. 1323 (1), 11-21, 10.1111/nyas.12441
6. Shlaes, D. M. (2015) Research and Development of Antibiotics: The Next Battleground. ACS Infect. Dis. 1 (6), 232-233, 10.1021/acsinfecdis.5b00048
7. Spellberg, B., Marr, K. A., and Brass, E. P. (2016) Regulatory Pathways for New Antimicrobial Agents: Trade-offs to Keep the Perfect From Being the Enemy of the Good. Clin. Pharmacol. Ther. 100 (6), 597-599, 10.1002/cpt.510
8. Gwynn, M. N., Portnoy, A., Rittenhouse, S. F., and Payne, D. J. (2010) Challenges of antibacterial discovery revisited. Ann. N. Y. Acad. Sci. 1213 (1), 5-19, 10.1111/j.1749-6632.2010.05828.x
9. Tommasi, R., Brown, D. G., Walkup, G. K., Manchester, J. I., and Miller, A. A. (2015) ESKAPEing the labyrinth of antibacterial discovery. Nat. Rev. Drug Discovery 14 (8), 529-42, 10.1038/nrd4572
10. Kostyanev, T., Bonten, M. J. M., O'Brien, S., Steel, H., Ross, S., François, B., Tacconelli, E., Winterhalter, M., Stavenger, R. A., Karlén, A., Harbarth, S., Hackett, J., Jafri, H. S., Vuong, C., MacGowan, A., Witschi, A., Angyalosi, G., Elborn, J. S., deWinter, R., and Goossens, H. (2016) The Innovative Medicines Initiative's New Drugs for Bad Bugs programme: European public-private partnerships for the development of new strategies to tackle antibiotic resistance. J. Antimicrob. Chemother. 71 (2), 290-295, 10.1093/jac/dkv339
11. Silver, L. L. (2016) A Gestalt approach to Gram-negative entry. Bioorg. Med. Chem. 24 (24), 6379-6389, 10.1016/j.bmc.2016.06.044
12. Pawlowski, A. C., Johnson, J. W., and Wright, G. D. (2016) Evolving medicinal chemistry strategies in antibiotic discovery. Curr. Opin. Biotechnol. 42 (Supplement C), 108-117, 10.1016/j.copbio.2016.04.006
13. Krishnamoorthy, G., Leus, I. V., Weeks, J. W., Wolloscheck, D., Rybenkov, V. V., and Zgurskaya, H. I. (2017) Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria. mBio 8 (5), e01172-17, 10.1128/mBio.01172-17
14. Shore, C., and Coukell, A. A Scientific Roadmap for Antibiotic Discovery; Pew Charitable Trusts: Washington, DC, 2016.
15. Payne, D. J., Gwynn, M. N., Holmes, D. J., and Pompliano, D. L. (2007) Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discovery 6, 29-40, 10.1038/nrd2201
16. Wang, J., Soisson, S. M., Young, K., Shoop, W., Kodali, S., Galgoci, A., Painter, R., Parthasarathy, G., Tang, Y. S., Cummings, R., Ha, S., Dorso, K., Motyl, M., Jayasuriya, H., Ondeyka, J., Herath, K., Zhang, C., Hernandez, L., Allocco, J., Basilio, á., Tormo, J. R., Genilloud, O., Vicente, F., Pelaez, F., Colwell, L., Lee, S. H., Michael, B., Felcetto, T., Gill, C., Silver, L. L., Hermes, J. D., Bartizal, K., Barrett, J., Schmatz, D., Becker, J. W., Cully, D., and Singh, S. B. (2006) Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature 441, 358-361, 10.1038/nature04784
17. Singh, S. B., Young, K., and Miesel, L. (2011) Screening strategies for discovery of antibacterial natural products. Expert Rev. Anti-Infect. Ther. 9 (8), 589-613, 10.1586/eri.11.81
18. O'Shea, R. and Moser, H. E. (2008) Physicochemical Properties of Antibacterial Compounds: Implications for Drug Discovery. J. Med. Chem. 51 (10), 2871-2878, 10.1021/jm700967e
19. Lipinski, C. A., Lombardo, F., Dominy, B. W., and Feeney, P. J. (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3-25.1. Adv. Drug Delivery Rev. 46 (1), 3-26, 10.1016/S0169-409X(00)00129-0
20. Nyfeler, B., Hoepfner, D., Palestrant, D., Kirby, C. A., Whitehead, L., Yu, R., Deng, G., Caughlan, R. E., Woods, A. L., Jones, A. K., Barnes, S. W., Walker, J. R., Gaulis, S., Hauy, E., Brachmann, S. M., Krastel, P., Studer, C., Riedl, R., Estoppey, D., Aust, T., Movva, N. R., Wang, Z., Salcius, M., Michaud, G. A., McAllister, G., Murphy, L. O., Tallarico, J. A., Wilson, C. J., and Dean, C. R. (2012) Identification of Elongation Factor G as the Conserved Cellular Target of Argyrin B. PLoS One 7 (9), e42657, 10.1371/journal.pone.0042657
21. Driggers, E. M., Hale, S. P., Lee, J., and Terrett, N. K. (2008) The exploration of macrocycles for drug discovery-an underexploited structural class. Nat. Rev. Drug Discovery 7, 608-624, 10.1038/nrd2590
22. Rezai, T., Yu, B., Millhauser, G. L., Jacobson, M. P., and Lokey, R. S. (2006) Testing the Conformational Hypothesis of Passive Membrane Permeability Using Synthetic Cyclic Peptide Diastereomers. J. Am. Chem. Soc. 128 (8), 2510-2511, 10.1021/ja0563455
23. Stone, G. G., Bradford, P. A., Yates, K., and Newell, P. (2017) In vitro activity of ceftazidime/avibactam against urinary isolates from patients in a Phase 3 clinical trial programme for the treatment of complicated urinary tract infections. J. Antimicrob. Chemother. 72 (5), 1396-1399, 10.1093/jac/dkw561
24. Durand-Réville, T. F., Guler, S., Comita-Prevoir, J., Chen, B., Bifulco, N., Huynh, H., Lahiri, S., Shapiro, A. B., McLeod, S. M., Carter, N. M., Moussa, S. H., Velez-Vega, C., Olivier, N. B., McLaughlin, R., Gao, N., Thresher, J., Palmer, T., Andrews, B., Giacobbe, R. A., Newman, J. V., Ehmann, D. E., de Jonge, B., O'Donnell, J., Mueller, J. P., Tommasi, R. A., and Miller, A. A. (2017) ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including. Acinetobacter baumannii. Nature Microbiology 2, 17104, 10.1038/nmicrobiol.2017.104
25. Brown, D. G., May-Dracka, T. L., Gagnon, M. M., and Tommasi, R. (2014) Trends and Exceptions of Physical Properties on Antibacterial Activity for Gram-Positive and Gram-Negative Pathogens. J. Med. Chem. 57 (23), 10144-10161, 10.1021/jm501552x
26. Richter, M. F., Drown, B. S., Riley, A. P., Garcia, A., Shirai, T., Svec, R. L., and Hergenrother, P. J. (2017) Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545, 299-304, 10.1038/nature22308
27. Quinn, J., Dudek, E., DiVincenzo, C., Lucks, D., and Lerner, S. (1986) Emergence of resistance to imipenem during therapy for Pseudomonas aeruginosa infections. J. Infect. Dis. 154 (2), 289-294, 10.1093/infdis/154.2.289
28. Trias, J. and Nikaido, H. (1990) Outer membrane protein D2 catalyzes facilitated diffusion of carbapenems and penems through the outer membrane of. Antimicrob. Agents Chemother. 34 (1), 52-57, 10.1128/AAC.34.1.52
29. Isabella, V. M., Campbell, A.J., Manchester, J., Sylvester, M., Nayar, A. S., Ferguson, K. E., Tommasi, R., and Miller, A. A (2015) Toward the Rational Design of Carbapenem Uptake in Pseudomonas aeruginosa. Chem. Biol. 22 (4), 535-547, 10.1016/j.chembiol.2015.03.018
30. Nikaido, H. (2003) Molecular Basis of Bacterial Outer Membrane Permeability Revisited. Microbiology and Molecular Biology Reviews 67 (4), 593-656, 10.1128/MMBR.67.4.593-656.2003
31. Hancock, R. E. W. and Brinkman, F. S. L. (2002) Function of Pseudomonas Porins in Uptake and Efflux. Annu. Rev. Microbiol. 56 (1), 17-38, 10.1146/annurev.micro.56.012302.160310
32. Lim, S. P. and Nikaido, H. (2010) Kinetic Parameters of Efflux of Penicillins by the Multidrug Efflux Transporter AcrAB-TolC of Escherichia coli. Antimicrob. Agents Chemother. 54 (5), 1800-1806, 10.1128/AAC.01714-09
33. Kojima, S. and Nikaido, H. (2013) Permeation rates of penicillins indicate that Escherichia coli porins function principally as nonspecific channels. Proc. Natl. Acad. Sci. U. S. A. 110 (28), E2629-E2634, 10.1073/pnas.1310333110
34. Yoshimura, F. and Nikaido, H. (1982) Permeability of Pseudomonas aeruginosa outer membrane to hydrophilic solutes. J. Bacteriol. 152 (2), 636-642
35. Tamber, S. and Hancock, R. E. W. (2003) On the mechanism of solute uptake in Pseudomonas. Front. Biosci., Landmark Ed. 8, s472-483, 10.2741/1075
36. Tamber, S., Ochs, M. M., and Hancock, R. E. W. (2006) Role of the Novel OprD Family of Porins in Nutrient Uptake in Pseudomonas aeruginosa. J. Bacteriol. 188 (1), 45-54, 10.1128/JB.188.1.45-54.2006
37. Eren, E., Parkin, J., Adelanwa, A., Cheneke, B., Movileanu, L., Khalid, S., and van den Berg, B. (2013) Toward Understanding the Outer Membrane Uptake of Small Molecules by Pseudomonas aeruginosa. J. Biol. Chem. 288 (17), 12042-12053, 10.1074/jbc.M113.463570
38. Zahn, M., Bhamidimarri, S. P., Baslé, A., Winterhalter, M., and van den Berg, B. (2016) Structural Insights into Outer Membrane Permeability of Acinetobacter baumannii. Structure 24 (2), 221-231, 10.1016/j.str.2015.12.009
39. Bajaj, H., Scorciapino, M. A., Moynié, L., Page, M. G. P., Naismith, J. H., Ceccarelli, M., and Winterhalter, M. (2016) Molecular Basis of Filtering Carbapenems by Porins from β-Lactam-resistant Clinical Strains of Escherichia coli. J. Biol. Chem. 291 (6), 2837-2847, 10.1074/jbc.M115.690156
40. Liu, J., Wolfe, A. J., Eren, E., Vijayaraghavan, J., Indic, M., van den Berg, B., and Movileanu, L. (2012) Cation Selectivity is a Conserved Feature in the OccD Subfamily of Pseudomonas aeruginosa. Biochim. Biophys. Acta, Biomembr. 1818 (11), 2908-2916, 10.1016/j.bbamem.2012.07.009
41. Liu, J., Eren, E., Vijayaraghavan, J., Cheneke, B. R., Indic, M., van den Berg, B., and Movileanu, L. (2012) OccK Channels from Pseudomonas aeruginosa Exhibit Diverse Single-Channel Electrical Signatures but Conserved Anion Selectivity. Biochemistry 51 (11), 2319-2330, 10.1021/bi300066w
42. Bajaj, H., Acosta Gutierrez, S., Bodrenko, I., Malloci, G., Scorciapino, M. A., Winterhalter, M., and Ceccarelli, M. (2017) Bacterial Outer Membrane Porins as Electrostatic Nanosieves: Exploring Transport Rules of Small Polar Molecules. ACS Nano 11 (6), 5465-5473, 10.1021/acsnano.6b08613
43. Bodrenko, I. V., Wang, J., Salis, S., Winterhalter, M., and Ceccarelli, M. (2017) Sensing Single Molecule Penetration into Nanopores: Pushing the Time Resolution to the Diffusion Limit. ACS Sensors 2 (8), 1184-1190, 10.1021/acssensors.7b00311
44. Ghai, I., Winterhalter, M., and Wagner, R. (2017) Probing transport of charged β-lactamase inhibitors through OmpC, a membrane channel from E. coli. Biochem. Biophys. Res. Commun. 484 (1), 51-55, 10.1016/j.bbrc.2017.01.076
45. Soundararajan, G., Bhamidimarri, S. P., and Winterhalter, M. (2017) Understanding Carbapenem Translocation through OccD3 (OpdP) of Pseudomonas aeruginosa. ACS Chem. Biol. 12 (6), 1656-1664, 10.1021/acschembio.6b01150
46. Mahendran, K. R., Kreir, M., Weingart, H., Fertig, N., and Winterhalter, M. (2010) Permeation of Antibiotics through Escherichia coli OmpF and OmpC Porins:Screening for Influx on a Single-Molecule Level. J. Biomol. Screening 15 (3), 302-307, 10.1177/1087057109357791
47. Nakashima, R., Sakurai, K., Yamasaki, S., Nishino, K., and Yamaguchi, A. (2011) Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket. Nature 480, 565-569, 10.1038/nature10641
48. Hinchliffe, P., Symmons, M. F., Hughes, C., and Koronakis, V. (2013) Structure and Operation of Bacterial Tripartite Pumps. Annu. Rev. Microbiol. 67 (1), 221-242, 10.1146/annurev-micro-092412-155718
49. Dreier, J., and Ruggerone, P. (2015) Interaction of antibacterial compounds with RND efflux pumps in Pseudomonas aeruginosa. Front. Microbiol. 6 (660); DOI: 10.3389/fmicb.2015.00660.
50. Daury, L., Orange, F., Taveau, J.-C., Verchère, A., Monlezun, L., Gounou, C., Marreddy, R. K. R., Picard, M., Broutin, I., Pos, K. M., and Lambert, O. (2016) Tripartite assembly of RND multidrug efflux pumps. Nat. Commun. 7, 10731, 10.1038/ncomms10731
51. Sjuts, H., Vargiu, A. V., Kwasny, S. M., Nguyen, S. T., Kim, H.-S., Ding, X., Ornik, A. R., Ruggerone, P., Bowlin, T. L., Nikaido, H., Pos, K. M., and Opperman, T. J. (2016) Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives. Proc. Natl. Acad. Sci. U. S. A. 113 (13), 3509-3514, 10.1073/pnas.1602472113
52. Nakashima, R., Sakurai, K., Yamasaki, S., Hayashi, K., Nagata, C., Hoshino, K., Onodera, Y., Nishino, K., and Yamaguchi, A. (2013) Structural basis for the inhibition of bacterial multidrug exporters. Nature 500, 102-106, 10.1038/nature12300
53. Wang, B., Weng, J., and Wang, W. (2015) Substrate binding accelerates the conformational transitions and substrate dissociation in multidrug efflux transporter AcrB. Front. Microbiol. 6 (302); DOI:) 10.3389/fmicb.2015.00302.
54. Cacciotto, P., Ramaswamy, V. K., Malloci, G., Ruggerone, P., and Vargiu, A. V. Molecular Modeling of Multidrug Properties of Resistance Nodulation Division (RND) Transporters. (2018) In Bacterial Multidrug Exporters: Methods and Protocols (Yamaguchi, A., and Nishino, K., Eds.), pp 179-219, Springer New York, New York, NY.
55. Fernández, L. and Hancock, R. E. W. (2012) Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance. Clin. Microbiol. Rev. 25 (4), 661-681, 10.1128/CMR.00043-12
56. Schweizer, H. P. (2012) Understanding efflux in Gram-negative bacteria: opportunities for drug discovery. Expert Opin. Drug Discovery 7 (7), 633-642, 10.1517/17460441.2012.688949
57. Blair, J. M., Richmond, G. E., and Piddock, L. J. (2014) Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. Future Microbiol. 9 (10), 1165-1177, 10.2217/fmb.14.66
58. Anes, J., McCusker, M. P., Fanning, S., and Martins, M. (2015) The ins and outs of RND efflux pumps in Escherichia coli. Front. Microbiol. 6, 587, 10.3389/fmicb.2015.00587
59. Li, X.-Z., Plésiat, P., and Nikaido, H. (2015) The Challenge of Efflux-Mediated Antibiotic Resistance in Gram-Negative Bacteria. Clin. Microbiol. Rev. 28 (2), 337-418, 10.1128/CMR.00117-14
60. Li, X. Z., Elkins, C. A., and Zgurskaya, H. I., Eds. (2016) Efflux-Mediated Antimicrobial Resistance in Bacteria: Mechanisms, Regulation and Clinical Implications, Springer International Publishing, Switzerland.
61. Nichols, W. W. (2017) Modeling the Kinetics of the Permeation of Antibacterial Agents into Growing Bacteria and Its Interplay with Efflux. Antimicrob. Agents Chemother. 61 (10), e02576-16, 10.1128/AAC.02576-16
62. Westfall, D. A., Krishnamoorthy, G., Wolloscheck, D., Sarkar, R., Zgurskaya, H. I., and Rybenkov, V. V. (2017) Bifurcation kinetics of drug uptake by Gram-negative bacteria. PLoS One 12 (9), e0184671, 10.1371/journal.pone.0184671
63. Iyer, R., Sylvester, M. A., Velez-Vega, C., Tommasi, R., Durand-Reville, T. F., and Miller, A. A. (2017) Whole-Cell-Based Assay To Evaluate Structure Permeation Relationships for Carbapenem Passage through the Pseudomonas aeruginosa Porin OprD. ACS Infect. Dis. 3 (4), 310-319, 10.1021/acsinfecdis.6b00197
64. Iyer, R., Moussa, S. H., Durand-Reville, T. F., Tommasi, R., and Miller, A. A. (2018) Acinetobacter baumannii OmpA is a selective antibiotic permeant porin. ACS Infect. Dis. 4 (3), 373-381, 10.1021/acsinfecdis.7b00168
65. Krishnamoorthy, G., Wolloscheck, D., Weeks, J. W., Croft, C., Rybenkov, V. V., and Zgurskaya, H. I. (2016) Breaking the Permeability Barrier of Escherichia coli by Controlled Hyperporination of the Outer Membrane. Antimicrob. Agents Chemother. 60 (12), 7372-7381, 10.1128/AAC.01882-16
66. Hilpert, K. and Hancock, R. E. W. (2007) Use of luminescent bacteria for rapid screening and characterization of short cationic antimicrobial peptides synthesized on cellulose using peptide array technology. Nat. Protoc. 2, 1652-1660, 10.1038/nprot.2007.203
67. Tran, Q.-T., Pearlstein, R. A., Williams, S., Reilly, J., Krucker, T., and Erdemli, G. (2014) Structure-kinetic relationship of carbapenem antibacterials permeating through E. coli OmpC porin. Proteins: Struct., Funct., Genet. 82 (11), 2998-3012, 10.1002/prot.24659
68. Miao, J., Hodgson, K. O., Ishikawa, T., Larabell, C. A., LeGros, M. A., and Nishino, Y. (2003) Imaging whole Escherichia coli bacteria by using single-particle x-ray diffraction. Proc. Natl. Acad. Sci. U. S. A. 100 (1), 110-112, 10.1073/pnas.232691299
69. Kaščáková, S., Maigre, L., Chevalier, J., Réfrégiers, M., and Pagès, J.-M. (2012) Antibiotic Transport in Resistant Bacteria: Synchrotron UV Fluorescence Microscopy to Determine Antibiotic Accumulation with Single Cell Resolution. PLoS One 7 (6), e38624, 10.1371/journal.pone.0038624
70. Heidari Torkabadi, H., Bethel, C. R., Papp-Wallace, K. M., de Boer, P. A. J., Bonomo, R. A., and Carey, P. R. (2014) Following Drug Uptake and Reactions inside Escherichia coli Cells by Raman Microspectroscopy. Biochemistry 53 (25), 4113-4121, 10.1021/bi500529c
71. Hong, S., Moritz, T. J., Rath, C. M., Tamrakar, P., Lee, P., Krucker, T., and Lee, L. P. (2017) Assessing Antibiotic Permeability of Gram-Negative Bacteria via Nanofluidics. ACS Nano 11 (7), 6959-6967, 10.1021/acsnano.7b02267
72. Tian, H., Six, D. A., Krucker, T., Leeds, J. A., and Winograd, N. (2017) Subcellular Chemical Imaging of Antibiotics in Single Bacteria Using C60-Secondary Ion Mass Spectrometry. Anal. Chem. 89 (9), 5050-5057, 10.1021/acs.analchem.7b00466
73. Zhou, Y., Joubran, C., Miller-Vedam, L., Isabella, V., Nayar, A., Tentarelli, S., and Miller, A. (2015) Thinking Outside the "Bug": A Unique Assay To Measure Intracellular Drug Penetration in Gram-Negative Bacteria. Anal. Chem. 87 (7), 3579-3584, 10.1021/ac504880r
74. Rath, C. M., Benton, B. M., de Vicente, J., Drumm, J. E., Geng, M., Li, C., Moreau, R. J., Shen, X., Skepper, C. K., Steffek, M., Takeoka, K., Wang, L., Wei, J.-R., Xu, W., Zhang, Q., and Feng, B. Y. (2018) Optimization of CoaD Inhibitors against Gram-Negative Organisms through Targeted Metabolomics. ACS Infect. Dis. 4 (3), 391-402, 10.1021/acsinfecdis.7b00214
75. Davis, T. D., Gerry, C. J., and Tan, D. S. (2014) General Platform for Systematic Quantitative Evaluation of Small-Molecule Permeability in Bacteria. ACS Chem. Biol. 9 (11), 2535-2544, 10.1021/cb5003015
76. Jansen, R. S. and Rhee, K. Y. (2017) Emerging Approaches to Tuberculosis Drug Development: At Home in the Metabolome. Trends Pharmacol. Sci. 38 (4), 393-405, 10.1016/j.tips.2017.01.005
77. Campbell, A. J., Sylvester, M., Isabella, V., Patey, S., Nayar, A., McLaughlin, B., MacCormack, K., Eyermann, J., Fleming, P., Basarab, G. A., deJonge, B., Gupta, A., Buurman, E., Chen, A., Mattes, K., Joubran, C., Doig, P., Sriram, S., Wesolowski, S., Durand-Reville, T., Ceccarelli, M., van den Berg, B., Huband, M., Miller, A., Mills, S., Manchester, J., Bisacchi, G., and Tommasi, R. (November 2013) In Improving our understanding of porin permeability in Gram-negative bacteria, Boston Area Antimicrobial Research Network (BAARN), Boston, MA 02451 USA.