Hybrid antibiotics – clinical progress and novel designs

Expert Opinion on Drug Discovery

Volumn 11, Issue 7, 2016, Pages 665-680

  Parkes, Alastair L ^a   Yule, Ian A ^a  

^a EVOTEC UK LTD   (United Kingdom)

Author keywords

Antibiotic resistance; Cadazolid; clinical progress; dual action drugs; hybrid antibiotics; multi targeting

Indexed keywords

AMINOGLYCOSIDE ANTIBIOTIC AGENT; ANTIBIOTIC AGENT; AZITHROMYCIN; CADAZOLID; CEFILAVANCIN; CEFTAROLINE; CEPHALOSPORIN; CEPHALOSPORIN DERIVATIVE; CIPROFLOXACIN; DAPTOMYCIN; FIDAXOMICIN; LEVOFLOXACIN; LINEZOLID; MCB 3681; MCB 3837; METRONIDAZOLE; MOXIFLOXACIN; POLYPEPTIDE ANTIBIOTIC AGENT; PRETOMANID; PYRAZINAMIDE; QUINOLINE DERIVED ANTIINFECTIVE AGENT; QUINOLONE DERIVATIVE; RIFAMPICIN; RIFAMYCIN; TD 1607; TD 1792; TEICOPLANIN; TOBRAMYCIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANCOMYCIN; ANTIINFECTIVE AGENT; OXAZOLIDINONE DERIVATIVE;

ANTIBACTERIAL ACTIVITY; ANTIBIOTIC RESISTANCE; ANTIBIOTIC THERAPY; BACTERIAL STRAIN; CLINICAL EVALUATION; CLINICAL TRIAL (TOPIC); CLOSTRIDIUM DIFFICILE INFECTION; COVALENT BOND; CYTOTOXICITY; DRUG DESIGN; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; GRAM NEGATIVE BACTERIUM; GRAM POSITIVE BACTERIUM; HUMAN; HYBRID; HYBRIDIZATION; IN VITRO STUDY; MEDICAL LITERATURE; MINIMUM INHIBITORY CONCENTRATION; MOLECULE; NONHUMAN; PHARMACOPHORE; PRIORITY JOURNAL; REVIEW; ANIMAL; BACTERIAL INFECTIONS; CHEMISTRY; MICROBIOLOGY; MULTIDRUG RESISTANCE;

ANIMALS; ANTI-BACTERIAL AGENTS; BACTERIAL INFECTIONS; DRUG DESIGN; DRUG RESISTANCE, MULTIPLE, BACTERIAL; HUMANS; OXAZOLIDINONES;

EID: 84975217786     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1080/17460441.2016.1187597     Document Type: Review

References (92)

1. C.Ash Antibiotic resistance: the new apocalypse? Trends Microbiol. 1996;4:371–372.
2. K.Grindrod. How the threat of antibiotic apocalypse helped a pharmacist find her voice. Can Pharm J. 2013;146:151–154. doi:10.1177/1715163513486864.
3. S.A.Waksman. What is an antibiotic or antibiotic substance? Mycologia. 1947;39:565–569. doi:10.2307/3755196.
4. L.Czaplewski, R.Bax, M.Clokie, et al. Alternatives to antibiotics — a pipeline portfolio review. Lancet Infect Dis. 2016;16(2):239–251. doi:10.1016/S1473-3099(15)00466-1.
5. S.M.Mandal, A.Roy, A.K.Ghosh, et al. Challenges and future prospects of antibiotic therapy: from peptides to phages utilization. Front Pharmacol. 2014;5(105):1–12. doi:10.3389/fphar.2014.00105.
6. A.H.Holmes, L.S.P.Moore, A.Sundsfjord, et al. Understanding the mechanisms and drivers of antimicrobial resistance. Lancet. 2016;387(10014):176–187. doi:10.1016/S0140-6736(15)00473-0.
7. J.Ho, P.A.Tambyah, D.L.Paterson. Multiresistant Gram-negative infections: a global perspective. Curr Opin Infect Dis. 2010;23:546–553. doi:10.1097/QCO.0b013e32833f0d3e.
8. G.H.Furtado, D.P.Nicolau. Overview perspective of bacterial resistance. Expert Opin Ther Pat. 2010;20:1273–1276. doi:10.1517/13543776.2010.507193.
9. K.Lewis. Platforms for antibiotic discovery. Nat Rev Drug Discov. 2013;12:371–387. doi:10.1038/nrd3975.
10. M.S.Kinch, E.Patridge, M.Plummer, et al. An analysis of FDA-approved drugs for infectious disease: antibacterial agents. Drug Discov Today. 2014;19:1283–1287. doi:10.1016/j.drudis.2014.07.005.
11. D.M.Livermore. Has the era of untreatable infections arrived? J Antimicrob Chemother. 2009;64:i29–i36. doi:10.1093/jac/dkp255.
12. R.J.Woods, A.F.Read. Clinical management of resistance evolution in a bacterial infection: a case study. Evol Med Public Heal. 2015;2015:281–288. doi:10.1093/emph/eov025.
13. L.L.Silver. Challenges of antibacterial discovery. Clin Microbiol Rev. 2011;24:71–109. doi:10.1128/CMR.00030-10.
14. S.M.Drawz, K.M.Papp-Wallace, R.A.Bonomo. New β-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother. 2014;58:1835–1846. doi:10.1128/AAC.02045-12.
15. C.Kourtesi, A.R.Ball, -Y.-Y.Huang, et al. Microbial efflux systems and inhibitors: approaches to drug discovery and the challenge of clinical implementation. Open Microbiol J. 2013;7:34–52. doi:10.2174/1874285801307010034.
16. A.Górska, A.Sloderbach, M.P.Marszałł. Siderophore-drug complexes: potential medicinal applications of the “Trojan horse” strategy. Trends Pharmacol Sci. 2014;35:442–449. doi:10.1016/j.tips.2014.06.007.
17. R.J.Worthington, C.Melander. Combination approaches to combat multi-drug resistant bacteria. Trends Biotechnol. 2013;31:177–184. doi:10.1016/j.tibtech.2012.12.006.
18. C.D.Doern. When does 2 plus 2 equal 5? A review of antimicrobial synergy testing. J Clin Microbiol. 2014;52:4124–4128. doi:10.1128/JCM.00749-14.
19. G.Cottarel, J.Wierzbowski. Combination drugs, an emerging option for antibacterial therapy. Trends Biotechnol. 2007;25:547–555. doi:10.1016/j.tibtech.2007.09.004.
20. P.D.Tamma, S.E.Cosgrove, L.L.Maragakis. Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev. 2012;25:450–470. doi:10.1128/CMR.05041-11.
21. R.Chait, A.Craney, R.Kishony. Antibiotic interactions that select against resistance. Nature. 2007;446:668–671. doi:10.1038/nature05685.
22. J.-B.Michel, P.J.Yeh, R.Chait, et al. Drug interactions modulate the potential for evolution of resistance. Proc Natl Acad Sci U S A. 2008;105:14918–14923. doi:10.1073/pnas.0800944105.
23. P.J.Yeh, M.J.Hegreness, A.P.Aiden, et al. Drug interactions and the evolution of antibiotic resistance. Nat Rev Microbiol. 2009;7:460–466. doi:10.1038/nrmicro2133.
24. V.Pokrovskaya, T.Baasov. Dual-acting hybrid antibiotics: a promising strategy to combat bacterial resistance. Expert Opin Drug Discov. 2010;5:883–902. doi:10.1517/17460441.2010.508069.•• An excellent introduction to the concept of dual-acting hybrid antibiotics, with a thorough discussion of the need to consider whether hybrids have synergistic or antagonistic activity and how this might affect development of resistance.
25. Y.Bansal, O.Silakari. Multifunctional compounds: smart molecules for multifactorial diseases. Eur J Med Chem. 2014;76:31–42. doi:10.1016/j.ejmech.2014.01.060.
26. M.Berbachyn. Recent advances in the discovery of hybrid antibacterial agents. Annu Rep Med Chem. 2008;43:281–290.
27. A.N.Tevyashova, E.N.Olsufyeva, M.N.Preobrazhenskaya. Design of dual action antibiotics as an approach to search for new promising drugs. Russ Chem Rev. 2015;84:61–97. doi:10.1070/RCR4448.
28. H.H.Locher, P.Seiler, X.Chen, et al. In vitro and in vivo antibacterial evaluation of Cadazolid, a new antibiotic for treatment of clostridium difficile infections. Antimicrob Agents Chemother. 2014;58:892–900. doi:10.1128/AAC.02045-12.•• An important disclosure on Cadazolid highlighting its in vitro antibacterial, anti-spore, and anti-toxin activity.
29. Actelion Pharmaceuticals. Clinical study to compare the efficacy and safety of Cadazolid versus Vancomycin in subjects with clostridium difficile-associated diarrhea. Clinical Trials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT01987895. [cited 2016 Jan17]. Available from: https://clinicaltrials.gov/show/NCT01987895
30. L.S.Tsutsumi, Y.B.Owusu, J.G.Hurdle, et al. Progress in the discovery of treatments for C. difficile infection: a clinical and medicinal chemistry review. Curr Top Med Chem. 2014;14:152–175.
31. A.M.Jarrad, T.Karoli, M.A.T.Blaskovich, et al. Clostridium difficile drug pipeline: challenges in discovery and development of new agents. J Med Chem. 2015;58:5164–5185. doi:10.1021/jm5016846.
32. H.H.Locher, P.Caspers, T.Bruyère, et al. Investigations of the mode of action and resistance development of cadazolid, a new antibiotic for treatment of Clostridium difficile infections. Antimicrob Agents Chemother. 2014;58:901–908. doi:10.1128/AAC.02045-12.
33. D.Baldoni, M.Gutierrez, W.Timmer, et al. Cadazolid, a novel antibiotic with potent activity against Clostridium difficile: safety, tolerability and pharmacokinetics in healthy subjects following single and multiple oral doses. J Antimicrob Chemother. 2014;69:706–714. doi:10.1093/jac/dkt401.
34. T.Louie, C.E.Nord, G.H.Talbot, et al. Multicenter, double-blind, randomized, phase 2 study evaluating the novel antibiotic Cadazolid in patients with clostridium difficile infection. Antimicrob Agents Chemother. 2015;59:6266–6273. doi:10.1128/AAC.00504-15.
35. D.N.Gerding, D.W.Hecht, T.Louie, et al. Susceptibility of Clostridium difficile isolates from a Phase 2 clinical trial of cadazolid and vancomycin in C. difficile infection. J Antimicrob Chemother. 2016;71:213–219. doi:10.1093/jac/dkv300.
36. F.C.Odds. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother. 2003;52:1. doi:10.1093/jac/dkg486.• Provides guidance on defining synergy and antagonism for combination therapy/hybrids.
37. Actelion Pharmaceuticals. Study to investigate the pharmacokinetics and safety of Cadazolid in patients with clostridium difficile infection. Clinical Trials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT02053181. [cited 2016 Jan17]. Available from: https://clinicaltrials.gov/show/NCT02053181
38. Actelion Pharmaceuticals. ACT-179811 in patients with clostridium difficile infection. Clinical Trials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT01222702. [cited 2016 Jan17]. Available from: https://clinicaltrials.gov/show/NCT01222702
39. J.Blais, S.R.Lewis, K.M.Krause, et al. Antistaphylococcal activity of TD-1792, a multivalent glycopeptide-cephalosporin antibiotic. Antimicrob Agents Chemother. 2012;56:1584–1587. doi:10.1128/AAC.06446-11.•• Primary reference describing the structure and in vitro activity of TD-1792.
40. Theravance Biopharma Antibiotics, Inc. TD-1792 in Gram-positive complicated skin and skin structure infection. Clinical Trials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT00442832. [cited 2016 Jan17]. Available from: https://clinicaltrials.gov/show/NCT00442832
41. M.E.Stryjewski, P.D.Potgieter, Y.-P.Li, et al. TD-1792 versus vancomycin for treatment of complicated skin and skin structure infections. Antimicrob Agents Chemother. 2012;56:5476–5483. doi:10.1128/AAC.06446-11.
42. Infectious disease programs, Theravance Biopharma website. 2016. [cited 2016 Jan17]. Available from: http://www.theravance.com/bacterial
43. K.L.Tyrrell, D.M.Citron, Y.A.Warren, et al. In vitro activity of TD-1792, a multivalent glycopeptide-cephalosporin antibiotic, against 377 strains of anaerobic bacteria and 34 strains of Corynebacterium species. Antimicrob Agents Chemother. 2012;56:2194–2197. doi:10.1128/AAC.06446-11.
44. S.S.Hegde, O.O.Okusanya, R.Skinner, et al. Pharmacodynamics of TD-1792, a novel glycopeptide-cephalosporin heterodimer antibiotic used against gram-positive bacteria, in a neutropenic murine thigh model. Antimicrob Agents Chemother. 2012;56:1578–1583. doi:10.1128/AAC.06446-11.
45. H.S.Sader, P.R.Rhomberg, D.J.Farrell, et al. Poster: Antimicrobial activity of TD-1607 tested against contemporary (2010-2012) methicillin-resistant staphylococcus aureus (MRSA) strains. Washington (DC): ICAAC; 2014.
46. Theravance Biopharma Antibiotics, Inc. TD-1607 SAD study in healthy subjects. Clinical Trials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT01791049. [cited 2016 Jan17]. Available from: https://clinicaltrials.gov/show/NCT01791049
47. Theravance Biopharma Antibiotics, Inc. TD-1607 MAD study in healthy subjects. Clinical Trials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000. NLM identifier: NCT01949103. [cited 2016 Jan17]. Available from: https://clinicaltrials.gov/show/NCT01949103
48. T.B.Doyle, E.J.Bonventre, Q.Du, et al. Poster: In vitro studies of the efficacy of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic, in killing staphylococcal cells in biofilms. Chicago (ILL): ICAAC; 2007.
49. G.T.Robertson, E.J.Bonventre, T.B.Doyle, et al. In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: studies of the mode of action in Staphylococcus aureus. Antimicrob Agents Chemother. 2008;52:2313–2323. doi:10.1128/AAC.01649-07.
50. H.G.Floss, T.-W.Yu. Rifamycin mode of action, resistance, and biosynthesis. Chem Rev. 2005;105:621–632. doi:10.1021/cr030112j.
51. G.T.Robertson, E.J.Bonventre, T.B.Doyle, et al. In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: microbiology profiling studies with staphylococci and streptococci. Antimicrob Agents Chemother. 2008;52:2324–2334. doi:10.1128/AAC.01651-07.
52. Cumbre announcement on completion of Phase I for CBR-2092. 2007. [cited 2016 Feb14]. Available from: http://www.prnewswire.com/news-releases/cumbre-announces-new-financing-58476467.html
53. R & D, Tenor Therapeutics website. 2016. [cited 2016 Feb14]. Available from: http://www.tennorx.com
54. S.Schubert, A.Dalhoff. Poster: low propensity for development of resistance to MCB3681, the active moiety of oxaquin (MCB3837), in gram-positive bacteria with vancomycin-, linezolid-, methicillin- and/or ciprofloxacin resistances. San Francisco (CA): ICAAC; 2006.
55. M.-U.Rashid, A.Dalhoff, A.Weintraub, et al. In vitro activity of MCB3681 against Clostridium difficile strains. Anaerobe. 2014;28:216–219. doi:10.1016/j.anaerobe.2014.07.001.
56. M.-U.Rashid, A.Dalhoff, T.Backstrom, et al. Ecological impact of MCB3837 on the normal human microbiota. Int J Antimicrob Agents. 2014;44:125–130. doi:10.1016/j.ijantimicag.2014.03.016.
57. A.Dalhoff, M.-U.Rashid, T.Kapsner, et al. Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle. Clin Microbiol Infect. 2015;21:767.e1–e767.e4. doi:10.1016/j.cmi.2015.05.025.
58. MCB3681 novel hybrid antibacterial, Morphochem AG website. 2016. [cited 2016 Feb14]. Available from: http://www.morphochem.de
59. B.K.Gorityala, G.Guchhait, D.M.Fernando, et al. Adjuvants based on hybrid antibiotics overcome resistance in pseudomonas aeruginosa and enhance fluoroquinolone efficacy. Angew Chemie Int Ed. 2016;55:555–559. doi:10.1002/anie.201508330.
60. X.-D.Wang, W.Wei, P.-F.Wang, et al. Novel 3-arylfuran-2(5H)-one-fluoroquinolone hybrid: design, synthesis and evaluation as antibacterial agent. Bioorg Med Chem. 2014;22:3620–3628. doi:10.1016/j.bmc.2014.05.018.• A rare example of a hybrid designed to have dual-action where activity at the targets of both parent antibiotics was demonstrated.
61. T.Plech, M.Wujec, A.Siwek, et al. Synthesis and antimicrobial activity of thiosemicarbazides, s-triazoles and their Mannich bases bearing 3-chlorophenyl moiety. Eur J Med Chem. 2011;46:241–248. doi:10.1016/j.ejmech.2010.11.010.
62. T.Plech, M.Wujec, U.Kosikowska, et al. Synthesis and in vitro activity of 1,2,4-triazole-ciprofloxacin hybrids against drug-susceptible and drug-resistant bacteria. Eur J Med Chem. 2013;60:128–134. doi:10.1016/j.ejmech.2012.11.040.
63. T.Plech, B.Kaproń, A.Paneth, et al. Determination of the primary molecular target of 1,2,4-Triazole-ciprofloxacin hybrids. Molecules. 2015;20:6254–6272. doi:10.3390/molecules20046254.
64. T.Plech, B.Kaproń, A.Paneth, et al. Search for factors affecting antibacterial activity and toxicity of 1,2,4-triazole-ciprofloxacin hybrids. Eur J Med Chem. 2015;97:94–103. doi:10.1016/j.ejmech.2015.04.058.
65. S.C.Ngo, O.Zimhony, J.C.Woo, et al. Inhibition of isolated Mycobacterium tuberculosis fatty acid synthase I by pyrazinamide analogs. Antimicrob Agents Chemother. 2007;51:2430–2435. doi:10.1128/AAC.01458-06.
66. S.D.Markad, P.Kaur, B.K.Kishore Reddy, et al. Novel lead generation of an anti-tuberculosis agent active against non-replicating mycobacteria: exploring hybridization of pyrazinamide with multiple fragments. Med Chem Res. 2015;24:2986–2992. doi:10.1007/s00044-015-1352-6.
67. A.G.Ross, B.M.Benton, D.Chin, et al. Synthesis of ciprofloxacin dimers for evaluation of bacterial permeability in atypical chemical space. Bioorg Med Chem Lett. 2015;25:3468–3475. doi:10.1016/j.bmcl.2015.07.010.
68. S.S.Panda, S.Liaqat, A.S.Girgis, et al. Novel antibacterial active quinolone–fluoroquinolone conjugates and 2D-QSAR studies. Bioorg Med Chem Lett. 2015;25:3816–3821. doi:10.1016/j.bmcl.2015.07.077.
69. Actelion Pharmaceuticals Ltd. Quinolone Derivatives. WO2014178008A1. 2014.
70. S.-F.Cui, L.-P.Peng, H.-Z.Zhang, et al. Novel hybrids of metronidazole and quinolones: synthesis, bioactive evaluation, cytotoxicity, preliminary antimicrobial mechanism and effect of metal ions on their transportation by human serum albumin. Eur J Med Chem. 2014;86:318–334. doi:10.1016/j.ejmech.2014.08.063.
71. D.Pavlovic, S.Mutak. Discovery of 4ʹ’-ether linked azithromycin-quinolone hybrid series: influence of the central linker on the antibacterial activity. ACS Med Chem Lett. 2011;2:331–336. doi:10.1021/ml100253p.
72. B.Findlay, G.G.Zhanel, F.Schweizer. Neomycin-phenolic conjugates: polycationic amphiphiles with broad-spectrum antibacterial activity, low hemolytic activity and weak serum protein binding. Bioorg Med Chem Lett. 2012;22:1499–1503. doi:10.1016/j.bmcl.2012.01.025.
73. S.Hanessian, J.P.Maianti, R.D.Matias, et al. Hybrid aminoglycoside antibiotics via tsuji palladium-catalyzed allylic deoxygenation. Org Lett. 2011;13:6476–6479. doi:10.1021/ol2026153.
74. J.P.Maianti, S.Hanessian. Structural hybridization of three aminoglycoside antibiotics yields a potent broad-spectrum bactericide that eludes bacterial resistance enzymes. Med Chem Commun. 2016;7:170–176. doi:10.1039/C5MD00429B.
75. D.F.Rakesh, Bruhn, M.S.Scherman, et al. Synthesis and evaluation of pretomanid (PA-824) oxazolidinone hybrids. Bioorg Med Chem Lett. 2016;26:388–391. doi:10.1016/j.bmcl.2016.03.080.
76. F.Yakushiji, Y.Miyamoto, Y.Kunoh, et al. Novel hybrid-type antimicrobial agents targeting the switch region of bacterial RNA polymerase. ACS Med Chem Lett. 2013;4:220–224. doi:10.1021/ml4003138.
77. F.Yakushiji, Y.Hayashi. Antibacterial agents containing hybrid molecule of myxopyronins and holothin and pharmaceutical compositions containing them. JP 2012201669. 2012.
78. S.J.Sucheck, A.L.Wong, K.M.Koeller, et al. Design of bifunctional antibiotics that target bacterial rRNA and inhibit resistance-causing enzymes. J Am Chem Soc. 2000;122:5230–5231. doi:10.1021/ja000575w.
79. Y.Berkov-Zrihen, K.D.Green, K.J.Labby, et al. 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;56:5613–5625. doi:10.1021/jm400707f.
80. S.S.Printsevskaya, M.I.Reznikova, A.M.Korolev, et al. Synthesis and study of antibacterial activities of antibacterial glycopeptide antibiotics conjugated with benzoxaboroles. Future Med Chem. 2013;5:641–652. doi:10.4155/fmc.13.16.
81. L.Chen, D.Yang, Z.Pan, et al. Synthesis and antimicrobial activity of the hybrid molecules between sulfonamides and active antimicrobial pleuromutilin derivative. Chem Biol Drug Des. 2015;86:239–245. doi:10.1111/cbdd.12561.
82. M.A.Silvers, G.T.Robertson, C.M.Taylor, et al. Design, synthesis, and antibacterial properties of dual-ligand inhibitors of acetyl-coa carboxylase. J Med Chem. 2014;57:8947–8959. doi:10.1021/jm401509e.• Design of a dual-ligand inhibitor of a multifunctional enzyme. A preferred hybrid had increased potency and reduced propensity for development of resistance.
83. F.-W.Zhou, H.-S.Lei, L.Fan, et al. Design, synthesis, and biological evaluation of dihydroartemisinin-fluoroquinolone conjugates as a novel type of potential antitubercular agents. Bioorg Med Chem Lett. 2014;24:1912–1917. doi:10.1016/j.bmcl.2014.03.010.
84. Y.Wang, G.L.V.Damu, J.S.Lv, et al. Design, synthesis and evaluation of clinafloxacin triazole hybrids as a new type of antibacterial and antifungal agents. Bioorganic Med Chem Lett. 2012;22:5363–5366. doi:10.1016/j.bmcl.2012.07.064.
85. X.-L.Gu, H.-B.Liu, Q.-H.Jia, et al. Design and synthesis of novel miconazole-based ciprofloxacin hybrids as potential antimicrobial agents. Monatshefte für Chemie Chem Mon. 2015;146:713–720. doi:10.1007/s00706-014-1364-9.
86. Z.-P.Xiao, X.-D.Wang, P.-F.Wang, et al. Design, synthesis, and evaluation of novel fluoroquinolone-flavonoid hybrids as potent antibiotics against drug-resistant microorganisms. Eur J Med Chem. 2014;80:92–100. doi:10.1016/j.ejmech.2014.04.037.
87. D.Tomkiewicz, G.Casadei, J.Larkins-Ford, et al. Berberine-INF55 (5-nitro-2-phenylindole) hybrid antimicrobials: effects of varying the relative orientation of the berberine and INF55 components. Antimicrob Agents Chemother. 2010;54:3219–3224. doi:10.1128/AAC.01715-09.
88. T.Zheng, E.M.Nolan. Enterobactin-mediated delivery of β-lactam antibiotics enhances antibacterial activity against pathogenic Escherichia coli. J Am Chem Soc. 2014;136:9677–9691. doi:10.1021/ja503911p.
89. T.A.Wencewicz, M.J.Miller. Biscatecholate–monohydroxamate mixed ligand siderophore–carbacephalosporin conjugates are selective sideromycin antibiotics that target acinetobacter baumannii. J Med Chem. 2013;56:4044–4052. doi:10.1021/jm400265k.
90. M.G.P.Page, C.Dantier, E.Desarbre. In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant Gram-negative Bacilli. Antimicrob Agents Chemother. 2010;54:2291–2302. doi:10.1128/AAC.01525-09.
91. C.Van Delden, M.G.P.Page, T.Köhler. Involvement of Fe uptake systems and AmpC β-lactamase in susceptibility to the siderophore monosulfactam BAL30072 in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2013;57:2095–2102. doi:10.1128/AAC.02474-12.
92. BAL30072, Basilea Pharmaceutica website. 2016. [cited 2016 Feb24] Available from: http://www.basilea.com/Portfolio/BAL30072