Overcoming Aminoglycoside Enzymatic Resistance: Design of Novel Antibiotics and Inhibitors

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2018 Feb 2

PMID 29385736

Citations 45

Authors

Sandra G Zarate

M Luisa De la Cruz Claure

Raul Benito-Arenas

Julia Revuelta

Andres G Santana

Agatha Bastida

Affiliations

Soon will be listed here.

Abstract

Resistance to aminoglycoside antibiotics has had a profound impact on clinical practice. Despite their powerful bactericidal activity, aminoglycosides were one of the first groups of antibiotics to meet the challenge of resistance. The most prevalent source of clinically relevant resistance against these therapeutics is conferred by the enzymatic modification of the antibiotic. Therefore, a deeper knowledge of the aminoglycoside-modifying enzymes and their interactions with the antibiotics and solvent is of paramount importance in order to facilitate the design of more effective and potent inhibitors and/or novel semisynthetic aminoglycosides that are not susceptible to modifying enzymes.

Citing Articles

Unveiling the nanoworld of antimicrobial resistance: integrating nature and nanotechnology.

Sharma D, Gautam S, Singh S, Srivastava N, Khan A, Bisht D Front Microbiol. 2025; 15():1391345.

PMID: 39850130 PMC: 11754303. DOI: 10.3389/fmicb.2024.1391345.

Evaluation of Antibiotic Resistance Mechanisms in Gram-Positive Bacteria.

Rajput P, Nahar K, Rahman K Antibiotics (Basel). 2025; 13(12.

PMID: 39766587 PMC: 11672434. DOI: 10.3390/antibiotics13121197.

Identification and characterization of a novel chromosome-encoded aminoglycoside -nucleotidyltransferase gene, in sp. TYF-12 isolated from the marine fish intestine.

Yu Y, Zhang R, Pan W, Sheng X, Chen S, Wang J Front Microbiol. 2024; 15:1475172.

PMID: 39726966 PMC: 11669914. DOI: 10.3389/fmicb.2024.1475172.

Natural Solutions to Antimicrobial Resistance: The Role of Essential Oils in Poultry Meat Preservation with Focus on Gram-Negative Bacteria.

Kovacevic Z, cabarkapa I, Saric L, Pajic M, Tomanic D, Kokic B Foods. 2024; 13(23).

PMID: 39682977 PMC: 11640364. DOI: 10.3390/foods13233905.

Environmental Antimicrobial Resistance: Implications for Food Safety and Public Health.

Ifedinezi O, Nnaji N, Anumudu C, Ekwueme C, Uhegwu C, Ihenetu F Antibiotics (Basel). 2024; 13(11).

PMID: 39596781 PMC: 11591122. DOI: 10.3390/antibiotics13111087.

References

Hainrichson M, Pokrovskaya V, Shallom-Shezifi D, Fridman M, Belakhov V, Shachar D . Branched aminoglycosides: biochemical studies and antibacterial activity of neomycin B derivatives. Bioorg Med Chem. 2005; 13(20):5797-807. DOI: 10.1016/j.bmc.2005.05.058. View

Hirsch D, Cox G, DErasmo M, Shakya T, Meck C, Mohd N . Inhibition of the ANT(2")-Ia resistance enzyme and rescue of aminoglycoside antibiotic activity by synthetic α-hydroxytropolones. Bioorg Med Chem Lett. 2014; 24(21):4943-7. PMC: 4798002. DOI: 10.1016/j.bmcl.2014.09.037. View

Pedersen L, Benning M, Holden H . Structural investigation of the antibiotic and ATP-binding sites in kanamycin nucleotidyltransferase. Biochemistry. 1995; 34(41):13305-11. DOI: 10.1021/bi00041a005. View

Nuthanakanti A, Boerneke M, Hermann T, Srivatsan S . Structure of the Ribosomal RNA Decoding Site Containing a Selenium-Modified Responsive Fluorescent Ribonucleoside Probe. Angew Chem Int Ed Engl. 2017; 56(10):2640-2644. PMC: 5397316. DOI: 10.1002/anie.201611700. View

Revuelta J, Vacas T, Corzana F, Gonzalez C, Bastida A, Asensio J . Structure-based design of highly crowded ribostamycin/kanamycin hybrids as a new family of antibiotics. Chemistry. 2010; 16(10):2986-91. DOI: 10.1002/chem.200903003. View

Livermore D . Fourteen years in resistance. Int J Antimicrob Agents. 2012; 39(4):283-94. DOI: 10.1016/j.ijantimicag.2011.12.012. View

Centron D, Roy P . Presence of a group II intron in a multiresistant Serratia marcescens strain that harbors three integrons and a novel gene fusion. Antimicrob Agents Chemother. 2002; 46(5):1402-9. PMC: 127176. DOI: 10.1128/AAC.46.5.1402-1409.2002. View

Williams J, Northrop D . Synthesis of a tight-binding, multisubstrate analog inhibitor of gentamicin acetyltransferase I. J Antibiot (Tokyo). 1979; 32(11):1147-54. DOI: 10.7164/antibiotics.32.1147. View

Berkov-Zrihen Y, Green K, Labby K, Feldman M, Garneau-Tsodikova S, Fridman M . Synthesis and evaluation of hetero- and homodimers of ribosome-targeting antibiotics: antimicrobial activity, in vitro inhibition of translation, and drug resistance. J Med Chem. 2013; 56(13):5613-25. PMC: 3823688. DOI: 10.1021/jm400707f. View

10.

Burk D, Hon W, Leung A, Berghuis A . Structural analyses of nucleotide binding to an aminoglycoside phosphotransferase. Biochemistry. 2001; 40(30):8756-64. DOI: 10.1021/bi010504p. View

11.

Boehr D, Draker K, Koteva K, Bains M, Hancock R, Wright G . Broad-spectrum peptide inhibitors of aminoglycoside antibiotic resistance enzymes. Chem Biol. 2003; 10(2):189-96. DOI: 10.1016/s1074-5521(03)00026-7. View

12.

Benveniste R, Davies J . R-factor mediated gentamicin resistance: A new enzyme which modifies aminoglycoside antibiotics. FEBS Lett. 1971; 14(5):293-296. DOI: 10.1016/0014-5793(71)80282-x. View

13.

Livermore D, Mushtaq S, Warner M, Zhang J, Maharjan S, Doumith M . Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother. 2010; 66(1):48-53. DOI: 10.1093/jac/dkq408. View

14.

Kotra L, Haddad J, Mobashery S . Aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance. Antimicrob Agents Chemother. 2000; 44(12):3249-56. PMC: 90188. DOI: 10.1128/AAC.44.12.3249-3256.2000. View

15.

Umezawa H, Umezawa S, Tsuchiya T, Okazaki Y . 3',4'-dideoxy-kanamycin B active against kanamycin-resistant Escherichia coli and Pseudomonas aeruginosa. J Antibiot (Tokyo). 1971; 24(7):485-7. DOI: 10.7164/antibiotics.24.485. View

16.

Van Pelt J, Northrop D . Purification and properties of gentamicin nucleotidyltransferase from Escherichia coli: nucleotide specificity, pH optimum, and the separation of two electrophoretic variants. Arch Biochem Biophys. 1984; 230(1):250-63. DOI: 10.1016/0003-9861(84)90106-1. View

17.

Brenner S . Phosphotransferase sequence homology. Nature. 1987; 329(6134):21. DOI: 10.1038/329021a0. View

18.

Pokrovskaya V, Nudelman I, Kandasamy J, Baasov T . Aminoglycosides redesign strategies for improved antibiotics and compounds for treatment of human genetic diseases. Methods Enzymol. 2010; 478:437-62. DOI: 10.1016/S0076-6879(10)78021-6. View

19.

Matesanz R, Diaz J, Corzana F, Santana A, Bastida A, Asensio J . Multiple keys for a single lock: the unusual structural plasticity of the nucleotidyltransferase (4')/kanamycin complex. Chemistry. 2012; 18(10):2875-89. DOI: 10.1002/chem.201101888. View

20.

Corzana F, Cuesta I, Bastida A, Hidalgo A, Latorre M, Gonzalez C . Molecular recognition of aminoglycoside antibiotics by bacterial defence proteins: NMR study of the structural and conformational features of streptomycin inactivation by Bacillus subtilis aminoglycoside-6-adenyl transferase. Chemistry. 2005; 11(17):5102-13. DOI: 10.1002/chem.200400941. View