Multidrug-resistant Gram-negative infections are dramatically on the rise as there has not been a novel class of antibiotics approved for these pathogens since 1968. We have been working to develop rules that can predict the types of compounds that are able to accumulate in Gram-negative bacteria, and we have recently published these rules and have applied them to convert the Gram-positive-only natural product antibiotic DNM into a version that also kills Gram-negative bacteria.
Related Publications:
- Computational discovery of dynobactin antibiotics
Munoz KA and Hergenrother PJ
Nature Microbiology 2022, 7, 1512-1513 (News and Views).
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- An iterative approach guides discovery of the FabI inhibitor fabimycin, a late-stage antibiotic candidate with in vivo efficacy against drug-resistant gram-negative infections
†Parker EN, †Cain BN, Hajian B, Ulrich RJ, Geddes EJ, Barkho S, Lee HY, Williams JD, Rynor M, Caridha D, Zaino A, Rodhe JM, Zak M, Shekhar M, Muñoz KA, Rzasa KM, Temple ER, Hunt D, Jin X, Vuong C, Pannone K, Kelly AM, Mulligan MP, Lee KK, Lau GW, Hung DT, Hergenrother PJ
ACS Cent. Sci. 2022, 8, 1145-1158
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- Role of internal loop dynamics in antibiotic permeability of outer membrane porins
Vasan, A.K.; Haloi, N.; Ulrich, R.J.; Metcalf, M.E.; Wen, P.C.; Metcalf, W.W.; Hergenrother, P.J.; Shukla, D.; Tajkhorshid, E.
Proc. Natl. Acad. Sci. 2022, 119, e2117009119
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- Rationalizing generation of broad spectrum antibiotics with the addition of a positive charge
Haloi, N.; Vasan, A.K.; Geddes, E.; Prasanna, A.; Wen, P.-C.; Metcalf, W.W.; Hergenrother, P.J.; Tajkhorshid, E.
Chem. Sci. 2021, 12, 15028
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- A LC-MS/MS assay and complementary web-based tool to quantify and predict compound accumulation in E. coli
Geddes, E.J; Li, Z.; Hergenrother, P.J.
Nature Protocols 2021, 16, 4833-4854.
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- Facilitating compound entry as a means to discover antibiotics for Gram-negative bacteria
Munoz, K.A. and Hergenrother, P.J.
Acc. Chem. Res. 2021, 54, 1322-1333.
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- Compound uptake into E. coli can be facilitated by N-alkyl guanidiniums and pyridinium
Perlmutter, S.J.; Geddes, E.J.; Drown, B.S.; Motika, S.E.; Lee, M.R.; Hergenrother, P.J.
ACS Infect. Dis., 2021, 7, 162-173.
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- A Gram-Negative Antibiotic Active Through Inhibition of an Essential Riboswitch
Motika, S. E; Ulrich, R. J.; Geddes, E. J.; Lee, H. Y.; Lau, G. W.; Hergenrother, P. J.
J. Am. Chem. Soc. 2020, 142, 10856-10862.
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- Implementation of permeation rules leads to a FabI inhibitor with activity against Gram-negative pathogens
Parker, E. N.; Drown, B. S.; Geddes, E. J.; Lee, H.-Y.; Ismail, N.; Lau, G. W. and Hergenrother, P. J.
Nature Microbiology 2020, 5, 67-75.
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Behind the paper
- The challenge of converting Gram-positive-only compounds into broad-spectrum antibiotics
Richter, M. F. and Hergenrother, P. J.
Ann NY Acad Sci. 2019, 1435, 18-38.
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- Going on offense against the Gram-negative defense
Drown, B.S. and Hergenrother, P. J.
Proc Natl. Acad. Sci. 2018, 115, 6530-6532.
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- Broad-Spectrum Antibiotics, a Call for Chemists
Richter, M. F.; Hergenrother, P. J.
Chem 2017, 3, 10-13 (essay).
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- Predictive Compound Accumulation Rules Yield a Broad-Spectrum Antibiotic
Richter, M. F.; Drown, B. S.; Riley, A. P.; Garcia, A.; Shirai, T.; Svec, R. L.; Hergenrother, P. J.
Nature 2017, 545, 299-304.
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