skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Toward the rational design of macrolide antibiotics to combat resistance

Abstract

Here, macrolides, one of the most prescribed classes of antibiotics, bind in the bacterial ribosome's polypeptide exit tunnel and inhibit translation. However, mutations and other ribosomal modifications, especially to the base A2058 of the 23S rRNA, have led to a growing resistance problem. Here, we have used molecular dynamics simulations to study the macrolides erythromycin and azithromycin in wild-type, A2058G-mutated, and singly or doubly A2058-methylated Escherichia coli ribosomes. We find that the ribosomal modifications result in less favorable interactions between the base 2058 and the desosamine sugar of the macrolides, as well as greater displacement of the macrolides from their crystal structure position, illuminating the causes of resistance. We have also examined four azithromycin derivatives containing aromatic indole-analog moieties, which were previously designed based on simulations of the stalling peptide SecM in the ribosome. Surprisingly, we found that the studied moieties could adopt very different geometries when interacting with a key base in the tunnel, A751, possibly explaining their distinct activities. Based on our simulations, we propose modifications to the indole-analog moieties that should increase their interactions with A751 and, consequently, enhance the potency of future azithromycin derivatives.

Authors:
 [1];  [2];  [1];  [1]
  1. Georgia Inst. of Technology, Atlanta, GA (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1376364
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
Chemical Biology & Drug Design
Additional Journal Information:
Journal Volume: 90; Journal Issue: 5; Journal ID: ISSN 1747-0277
Publisher:
Wiley
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; antibiotics; drug design; macrolides; molecular modeling; ribosome

Citation Formats

Pavlova, Anna, Parks, Jerry M., Oyelere, Adegboyega K., and Gumbart, James C. Toward the rational design of macrolide antibiotics to combat resistance. United States: N. p., 2017. Web. doi:10.1111/cbdd.13004.
Pavlova, Anna, Parks, Jerry M., Oyelere, Adegboyega K., & Gumbart, James C. Toward the rational design of macrolide antibiotics to combat resistance. United States. doi:10.1111/cbdd.13004.
Pavlova, Anna, Parks, Jerry M., Oyelere, Adegboyega K., and Gumbart, James C. Mon . "Toward the rational design of macrolide antibiotics to combat resistance". United States. doi:10.1111/cbdd.13004. https://www.osti.gov/servlets/purl/1376364.
@article{osti_1376364,
title = {Toward the rational design of macrolide antibiotics to combat resistance},
author = {Pavlova, Anna and Parks, Jerry M. and Oyelere, Adegboyega K. and Gumbart, James C.},
abstractNote = {Here, macrolides, one of the most prescribed classes of antibiotics, bind in the bacterial ribosome's polypeptide exit tunnel and inhibit translation. However, mutations and other ribosomal modifications, especially to the base A2058 of the 23S rRNA, have led to a growing resistance problem. Here, we have used molecular dynamics simulations to study the macrolides erythromycin and azithromycin in wild-type, A2058G-mutated, and singly or doubly A2058-methylated Escherichia coli ribosomes. We find that the ribosomal modifications result in less favorable interactions between the base 2058 and the desosamine sugar of the macrolides, as well as greater displacement of the macrolides from their crystal structure position, illuminating the causes of resistance. We have also examined four azithromycin derivatives containing aromatic indole-analog moieties, which were previously designed based on simulations of the stalling peptide SecM in the ribosome. Surprisingly, we found that the studied moieties could adopt very different geometries when interacting with a key base in the tunnel, A751, possibly explaining their distinct activities. Based on our simulations, we propose modifications to the indole-analog moieties that should increase their interactions with A751 and, consequently, enhance the potency of future azithromycin derivatives.},
doi = {10.1111/cbdd.13004},
journal = {Chemical Biology & Drug Design},
number = 5,
volume = 90,
place = {United States},
year = {2017},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Save / Share:

Works referenced in this record:

Components of the macrolide binding site on the ribosome
journal, January 1985

  • Tejedor, F.; Ballesta, J. P. G.
  • Journal of Antimicrobial Chemotherapy, Vol. 16, Issue suppl A
  • DOI: 10.1093/jac/16.suppl_A.53

Sequence selectivity of macrolide-induced translational attenuation
journal, October 2014

  • Davis, A. R.; Gohara, D. W.; Yap, M. -N. F.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 43
  • DOI: 10.1073/pnas.1410356111

Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B
journal, October 2013

  • Vincent, Benjamin Matteson; Lancaster, Alex Kelvin; Scherz-Shouval, Ruth
  • PLoS Biology, Vol. 11, Issue 10
  • DOI: 10.1371/journal.pbio.1001692

Revisiting the structures of several antibiotics bound to the bacterial ribosome
journal, September 2010

  • Bulkley, D.; Innis, C. A.; Blaha, G.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 40
  • DOI: 10.1073/pnas.1008685107

Free and bound state structures of 6-O-methyl homoerythromycins and epitope mapping of their interactions with ribosomes
journal, August 2009

  • Novak, Predrag; Barber, Jill; Čikoš, Ana
  • Bioorganic & Medicinal Chemistry, Vol. 17, Issue 16
  • DOI: 10.1016/j.bmc.2009.07.013

Synthesis and antibacterial activity of desosamine-modified macrolide derivatives
journal, July 2012

  • LeTourneau, Nicolas; Vimal, Pavan; Klepacki, Dorota
  • Bioorganic & Medicinal Chemistry Letters, Vol. 22, Issue 14
  • DOI: 10.1016/j.bmcl.2012.05.110

Release of (oligo) peptidyl-tRNA from ribosomes by erythromycin A.
journal, July 1975

  • Otaka, T.; Kaji, A.
  • Proceedings of the National Academy of Sciences, Vol. 72, Issue 7
  • DOI: 10.1073/pnas.72.7.2649

Mycoplasma pneumoniae 23S rRNA Gene Mutations and Mechanisms of Macrolide Resistance
journal, February 2013


Optimization of the CHARMM Additive Force Field for DNA: Improved Treatment of the BI/BII Conformational Equilibrium
journal, December 2011

  • Hart, Katarina; Foloppe, Nicolas; Baker, Christopher M.
  • Journal of Chemical Theory and Computation, Vol. 8, Issue 1
  • DOI: 10.1021/ct200723y

Scalable molecular dynamics with NAMD
journal, January 2005

  • Phillips, James C.; Braun, Rosemary; Wang, Wei
  • Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802
  • DOI: 10.1002/jcc.20289

Diversity of Ribosomal Mutations Conferring Resistance to Macrolides, Clindamycin, Streptogramin, and Telithromycin in Streptococcus pneumoniae
journal, January 2002


The ABC of Ribosome-Related Antibiotic Resistance
journal, May 2016


Macrolide antibiotics in the ribosome exit tunnel: species-specific binding and action: Species-specific binding and action of macrolides
journal, December 2011


Resistance to the macrolide antibiotic tylosin is conferred by single methylations at 23S rRNA nucleotides G748 and A2058 acting in synergy
journal, November 2002

  • Liu, M.; Douthwaite, S.
  • Proceedings of the National Academy of Sciences, Vol. 99, Issue 23
  • DOI: 10.1073/pnas.232580599

Mechanisms of resistance to telithromycin in Streptococcus pneumoniae
journal, July 2005

  • Hisanaga, Tamiko; Hoban, Daryl J.; Zhanel, George G.
  • Journal of Antimicrobial Chemotherapy, Vol. 56, Issue 3
  • DOI: 10.1093/jac/dki249

Structures of the Escherichia coli ribosome with antibiotics bound near the peptidyl transferase center explain spectra of drug action
journal, September 2010

  • Dunkle, J. A.; Xiong, L.; Mankin, A. S.
  • Proceedings of the National Academy of Sciences, Vol. 107, Issue 40
  • DOI: 10.1073/pnas.1007988107

Binding and Action of CEM-101, a New Fluoroketolide Antibiotic That Inhibits Protein Synthesis
journal, September 2010

  • Llano-Sotelo, B.; Dunkle, J.; Klepacki, D.
  • Antimicrobial Agents and Chemotherapy, Vol. 54, Issue 12
  • DOI: 10.1128/AAC.00860-10

The macrolide-ketolide antibiotic binding site is formed by structures in domains II and V of 23S ribosomal RNA
journal, January 1999


Comparison of simple potential functions for simulating liquid water
journal, July 1983

  • Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.
  • The Journal of Chemical Physics, Vol. 79, Issue 2
  • DOI: 10.1063/1.445869

Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size
journal, August 2016


Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA
journal, April 2000


Systematic Approach to Understanding Macrolide−Ribosome Interactions:  NMR and Modeling Studies of Oleandomycin and Its Derivatives
journal, January 2006

  • Novak, Predrag; Tatić, Iva; Tepeš, Predrag
  • The Journal of Physical Chemistry A, Vol. 110, Issue 2
  • DOI: 10.1021/jp0526243

Macrolide Resistance Conferred by Base Substitutions in 23S rRNA
journal, January 2001


Binding Site of Macrolide Antibiotics on the Ribosome: New Resistance Mutation Identifies a Specific Interaction of Ketolides with rRNA
journal, December 2001


Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom Typing
journal, November 2012

  • Vanommeslaeghe, K.; MacKerell, A. D.
  • Journal of Chemical Information and Modeling, Vol. 52, Issue 12
  • DOI: 10.1021/ci300363c

Interplay between the Ribosomal Tunnel, Nascent Chain, and Macrolides Influences Drug Inhibition
journal, May 2010


Role of antibiotic ligand in nascent peptide-dependent ribosome stalling
journal, June 2011

  • Vazquez-Laslop, N.; Klepacki, D.; Mulhearn, D. C.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 26
  • DOI: 10.1073/pnas.1103474108

Estimates of the Ab Initio Limit for π−π Interactions:  The Benzene Dimer
journal, September 2002

  • Sinnokrot, Mutasem Omar; Valeev, Edward F.; Sherrill, C. David
  • Journal of the American Chemical Society, Vol. 124, Issue 36
  • DOI: 10.1021/ja025896h

Rapid parameterization of small molecules using the force field toolkit
journal, September 2013

  • Mayne, Christopher G.; Saam, Jan; Schulten, Klaus
  • Journal of Computational Chemistry, Vol. 34, Issue 32
  • DOI: 10.1002/jcc.23422

Development and testing of a general amber force field
journal, January 2004

  • Wang, Junmei; Wolf, Romain M.; Caldwell, James W.
  • Journal of Computational Chemistry, Vol. 25, Issue 9
  • DOI: 10.1002/jcc.20035

Parametrization of macrolide antibiotics using the force field toolkit
journal, August 2015

  • Pavlova, Anna; Gumbart, James C.
  • Journal of Computational Chemistry, Vol. 36, Issue 27
  • DOI: 10.1002/jcc.24043

Automation of the CHARMM General Force Field (CGenFF) II: Assignment of Bonded Parameters and Partial Atomic Charges
journal, November 2012

  • Vanommeslaeghe, K.; Raman, E. Prabhu; MacKerell, A. D.
  • Journal of Chemical Information and Modeling, Vol. 52, Issue 12
  • DOI: 10.1021/ci3003649

Improving the Force Field Description of Tyrosine–Choline Cation−π Interactions: QM Investigation of Phenol–N(Me) 4 + Interactions
journal, October 2016

  • Khan, Hanif M.; Grauffel, Cédric; Broer, Ria
  • Journal of Chemical Theory and Computation, Vol. 12, Issue 11
  • DOI: 10.1021/acs.jctc.6b00654

Rethinking the term “pi-stacking”
journal, January 2012

  • Martinez, Chelsea R.; Iverson, Brent L.
  • Chemical Science, Vol. 3, Issue 7
  • DOI: 10.1039/c2sc20045g

In Vitro Activity of the New Fluoroketolide Solithromycin (CEM-101) against Macrolide-Resistant and -Susceptible Mycoplasma genitalium Strains
journal, March 2014

  • Jensen, Jørgen Skov; Fernandes, Prabhavathi; Unemo, Magnus
  • Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 6
  • DOI: 10.1128/AAC.02411-14

Accurate Coulomb-fitting basis sets for H to Rn
journal, January 2006

  • Weigend, Florian
  • Physical Chemistry Chemical Physics, Vol. 8, Issue 9
  • DOI: 10.1039/b515623h

A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu
journal, April 2010

  • Grimme, Stefan; Antony, Jens; Ehrlich, Stephan
  • The Journal of Chemical Physics, Vol. 132, Issue 15
  • DOI: 10.1063/1.3382344

The Structures of Four Macrolide Antibiotics Bound to the Large Ribosomal Subunit
journal, July 2002


Mechanisms of SecM-Mediated Stalling in the Ribosome
journal, July 2012

  • Gumbart, James; Schreiner, Eduard; Wilson, Daniel N.
  • Biophysical Journal, Vol. 103, Issue 2
  • DOI: 10.1016/j.bpj.2012.06.005

Molecular characterization of macrolide resistance mechanisms among Streptococcus pneumoniae and Streptococcus pyogenes isolated from the PROTEKT 1999-2000 study
journal, September 2002

  • Farrell, D. J.; Morrissey, I.; Bakker, S.
  • Journal of Antimicrobial Chemotherapy, Vol. 50, Issue suppl 2
  • DOI: 10.1093/jac/dkf806

Benchmarking Density Functional Methods against the S66 and S66x8 Datasets for Non-Covalent Interactions
journal, November 2011


Structural Basis for the Antibiotic Activity of Ketolides and Azalides
journal, March 2003


Erythromycin Binding is Reduced in Ribosomes with Conformational Alterations in the 23 S rRNA Peptidyl Transferase Loop
journal, August 1993

  • Douthwaite, Stephen; Aagaard, Claus
  • Journal of Molecular Biology, Vol. 232, Issue 3
  • DOI: 10.1006/jmbi.1993.1426

Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy
journal, January 2005

  • Weigend, Florian; Ahlrichs, Reinhart
  • Physical Chemistry Chemical Physics, Vol. 7, Issue 18, p. 3297-3305
  • DOI: 10.1039/b508541a

Additive CHARMM force field for naturally occurring modified ribonucleotides: CHARMM Potential Energy Function
journal, February 2016

  • Xu, You; Vanommeslaeghe, Kenno; Aleksandrov, Alexey
  • Journal of Computational Chemistry, Vol. 37, Issue 10
  • DOI: 10.1002/jcc.24307

Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus
journal, October 2015

  • Eyal, Zohar; Matzov, Donna; Krupkin, Miri
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 43
  • DOI: 10.1073/pnas.1517952112

S66: A Well-balanced Database of Benchmark Interaction Energies Relevant to Biomolecular Structures
journal, July 2011

  • Řezáč, Jan; Riley, Kevin E.; Hobza, Pavel
  • Journal of Chemical Theory and Computation, Vol. 7, Issue 8
  • DOI: 10.1021/ct2002946

Antimicrobial activity of RU-66647, a new ketolide
journal, January 1997


Particle mesh Ewald: An N ⋅log( N ) method for Ewald sums in large systems
journal, June 1993

  • Darden, Tom; York, Darrin; Pedersen, Lee
  • The Journal of Chemical Physics, Vol. 98, Issue 12
  • DOI: 10.1063/1.464397

Conjugates of Amino Acids and Peptides with 5- O -Mycaminosyltylonolide and Their Interaction with the Ribosomal Exit Tunnel
journal, October 2013

  • Shishkina, Anna; Makarov, Gennady; Tereshchenkov, Andrey
  • Bioconjugate Chemistry, Vol. 24, Issue 11
  • DOI: 10.1021/bc400236n

Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ 1 and χ 2 Dihedral Angles
journal, August 2012

  • Best, Robert B.; Zhu, Xiao; Shim, Jihyun
  • Journal of Chemical Theory and Computation, Vol. 8, Issue 9
  • DOI: 10.1021/ct300400x

Molecular Insights into 14-Membered Macrolides Using the MM-PBSA Method
journal, May 2009

  • Yam, Wai Keat; Wahab, Habibah A.
  • Journal of Chemical Information and Modeling, Vol. 49, Issue 6
  • DOI: 10.1021/ci8003495

Structure and energetics of ligand binding to proteins:Escherichia coli dihydrofolate reductase-trimethoprim, a drug-receptor system
journal, January 1988

  • Dauber-Osguthorpe, Pnina; Roberts, Victoria A.; Osguthorpe, David J.
  • Proteins: Structure, Function, and Genetics, Vol. 4, Issue 1
  • DOI: 10.1002/prot.340040106

Erythromycin resistance by ribosome modification
journal, March 1995


Accelerating molecular modeling applications with graphics processors
journal, January 2007

  • Stone, John E.; Phillips, James C.; Freddolino, Peter L.
  • Journal of Computational Chemistry, Vol. 28, Issue 16
  • DOI: 10.1002/jcc.20829

Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against gram-negative organisms.
journal, December 1987

  • Retsema, J.; Girard, A.; Schelkly, W.
  • Antimicrobial Agents and Chemotherapy, Vol. 31, Issue 12
  • DOI: 10.1128/AAC.31.12.1939

Macrolide antibiotics allosterically predispose the ribosome for translation arrest
journal, June 2014

  • Sothiselvam, Shanmugapriya; Liu, Bo; Han, Wei
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 27
  • DOI: 10.1073/pnas.1403586111

The general mode of translation inhibition by macrolide antibiotics
journal, October 2014

  • Kannan, Krishna; Kanabar, Pinal; Schryer, David
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 45
  • DOI: 10.1073/pnas.1417334111

Molecular modeling of 5-desacetylaltohyrtin A, a spongean cytotoxic macrolide
journal, March 2001


Unexpected Substituent Effects in Face-to-Face π-Stacking Interactions
journal, October 2003

  • Sinnokrot, Mutasem Omar; Sherrill, C. David
  • The Journal of Physical Chemistry A, Vol. 107, Issue 41
  • DOI: 10.1021/jp030880e

Mutations in 23S rRNA and Ribosomal Protein L4 Account for Resistance in Pneumococcal Strains Selected In Vitro by Macrolide Passage
journal, August 2000


Ab Initio Molecular Orbital and Density Functional Studies on the Stable Structures and Vibrational Properties of trans - and cis -Azobenzenes
journal, August 2000

  • Kurita, Noriyuki; Tanaka, Shigenori; Itoh, Satoshi
  • The Journal of Physical Chemistry A, Vol. 104, Issue 34
  • DOI: 10.1021/jp001307n

Mechanisms of Resistance to Macrolides and Lincosamides: Nature of the Resistance Elements and Their Clinical Implications
journal, February 2002

  • Leclercq, Roland
  • Clinical Infectious Diseases, Vol. 34, Issue 4
  • DOI: 10.1086/324626

Ketolide resistance in Streptococcus pyogenes correlates with the degree of rRNA dimethylation by Erm : Ketolide resistance and dimethylation by Erm
journal, September 2005


Insights into resistance mechanism of the macrolide biosensor protein MphR(A) binding to macrolide antibiotic erythromycin by molecular dynamics simulation
journal, November 2015

  • Feng, Tingting; Zhang, Yanjun; Ding, Jing-Na
  • Journal of Computer-Aided Molecular Design, Vol. 29, Issue 12
  • DOI: 10.1007/s10822-015-9881-0

Unnatural Amino Acid Mutagenesis of Green Fluorescent Protein
journal, November 2002

  • Wang, Lei; Xie, Jianming; Deniz, Ashok A.
  • The Journal of Organic Chemistry, Vol. 68, Issue 1, p. 174-176
  • DOI: 10.1021/jo026570u

The Mechanism of Action of Macrolides, Lincosamides and Streptogramin B Reveals the Nascent Peptide Exit Path in the Ribosome
journal, July 2003


Erythromycin, carbomycin, and spiramycin inhibit protein synthesis by stimulating the dissociation of peptidyl-tRNA from ribosomes.
journal, May 1982

  • Menninger, J. R.; Otto, D. P.
  • Antimicrobial Agents and Chemotherapy, Vol. 21, Issue 5
  • DOI: 10.1128/AAC.21.5.811

Macrolide-Peptide Conjugates as Probes of the Path of Travel of the Nascent Peptides through the Ribosome
journal, September 2014

  • Washington, Arren Z.; Benicewicz, Derek B.; Canzoneri, Joshua C.
  • ACS Chemical Biology, Vol. 9, Issue 11
  • DOI: 10.1021/cb5003224

The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors
journal, October 1970


Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump
journal, November 2016


Selective Protein Synthesis by Ribosomes with a Drug-Obstructed Exit Tunnel
journal, October 2012


VMD: Visual molecular dynamics
journal, February 1996