Novel Gram-Negative Antibiotics

Multidrug-resistant Gram-negative infections are dramatically on the rise, as there has not been a novel class of antibiotics FDA approved for these pathogens since 1968.  We have been developing rules to predict the types of compounds that accumulate in Gram-negative bacteria, and we have been using these rules to design novel antibiotics active against Gram-negative pathogens.

Related Publications:

  1. A Gram-negative-selective antibiotic that spares the gut microbiome
    Muñoz KA, Ulrich RJ, Vasan AK, Sinclair M, Wen P-C, Holmes JR, , Lee HY, Hung C-C, Fields CJ, Tajkhorshid E, Lau GW, Hergenrother PJ
    Nature 2024, 630, 429-436
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  1. Using permeation guidelines to design new antibiotics – a PASsagE into Pseudomonas aeruginosa
    Cain BN and Hergenrother PJ
    Clin. Transl. Med. 2024, 4, e1600

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  1. New antibiotic targets a drug-resistant bacterium
    Gugger MK and Hergenrother PJ
    Nature 2024, 625, 451-452 (News & Views)

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  1. Porin-independent accumulation in Pseudomonas enables antibiotic discovery
    Geddes EJ, Gugger MK, Garcia A, Chavez MG, Lee MR, Perlmutter SJ, Bieniossek C, Guasch L, Hergenrother PJ
    Nature 2023, 624, 145-153

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UIUC Press Release

  1. Computational discovery of dynobactin antibiotics
    Munoz KA and Hergenrother PJ
    Nature Microbiology 2022, 7, 1512-1513 (News and Views).

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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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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  1. 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
  1. 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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  1. 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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  1. Broad-Spectrum Antibiotics, a Call for Chemists
    Richter, M. F.; Hergenrother, P. J.
    Chem 2017, 3, 10-13 (essay).

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  1. 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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