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Peptide-Antibiotic Conjugates As Novel Developments for Increased Antimicrobial Transport and Efficiency

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Peptide-Antibiotic Conjugates As Novel Developments for Increased Antimicrobial Transport and Efficiency PEPTIDE-ANTIBIOTIC CONJUGATES AS NOVEL DEVELOPMENTS FOR INCREASED ANTIMICROBIAL TRANSPORT AND EFFICIENCY Belina Sithole MSc by Research University of York Chemistry December 2015 Abstract The emergence of bacterial strains with resistance to most known antibiotics has raised an urgent need for the development of new antimicrobial agents in order to avoid a serious threat to public health and return to the pre-antibiotic era. The ‘Trojan Horse’ strategy is one of the approaches that has been explored to evade membrane – based resistance mechanisms by smuggling the antibiotic in through the bacterial cell membrane(s). The ‘Trojan Horse’ strategy involves conjugating a siderophore, sugar or an amino acid moiety to an antimicrobial agent to allow more effective antimicrobial transport. They can be conjugated through a non-biolabile or a biolabile linker; both types of the ‘Trojan Horse’ conjugates were prepared based on the antibiotic ciprofloxacin and alanine (Ala) and di-alanine (Ala-Ala). The conjugates were screened against wild type E. coli to compare the minimum inhibitory concentrations (MIC)/minimum bacterial concentrations with those of the free parent drug ciprofloxacin. The conjugate coupled through a non-biolabile linker, Ala-Ala-ciprofloxacin, was found to have a very significant reduced antimicrobial activity compared to the parent drug with no evidence of active transport by peptide transporters. A DNA gyrase assay revealed that the conjugate was no longer an effective DNA gyrase-inhibitor. The conjugates coupled through the biolabile disulfide linker, ciprofloxacin- disulfide-Ala and ciprofloxacin-disulfide-Ala-Ala, were found to have retained some antimicrobial activity although lower than that of the parent drug. The conjugates reached a peak OD650 of 3.0 at 0.1 μM whereas ciprofloxacin reached a peak OD650 of 1.0 at the same concentration. No evidence of transport by peptide transporters was observed. The retained antimicrobial activity suggested that intracellular cleavage of the disulfide linker occurred releasing free ciprofloxacin however the reduced antimicrobial activity could be due to inefficient cleavage of the disulfide bond or inefficient intracellular release of ciprofloxacin due to slow formation of the thiirane ring allowing re-formation of a disulfide bond. 2 Table of contents Abstract .................................................................................................................................................. 2 Contents ................................................................................................................................................. 3 List of figures ........................................................................................................................................... 6 List of schemes ........................................................................................................................................ 9 List of tables .......................................................................................................................................... 11 Acknowledgements………………………………………………………………………………….……………….………………12 Declaration ............................................................................................................................................ 13 1. Introduction ...................................................................................................................................... 14 1.1. Antibiotics ................................................................................................................................... 14 1.1.1. Antibacterial resistance ...................................................................................................... 14 1.1.2. Alteration/modification of the intracellular target site ...................................................... 15 1.1.3. Antibiotic inactivation/degradation .................................................................................... 16 1.1.4. Efflux pumps ....................................................................................................................... 17 1.1.5. Reduced permeability ......................................................................................................... 17 1.1.6. Overcoming bacterial resistance……………………………………………………………….……………...17 1.1.6.1. Combination therapy ..................................................................................................... 18 1.1.6.2. Overcoming membrane-based resistance ...................................................................... 18 1.2. Introduction to fluoroquinolones ……….……………………………………………………………….………….19 1.2.1. Development of fluoroquinolones ....................................................................................... 21 1.2.2. Mode of action of DNA gyrase……………………..…………………..…………..……………………….…22 1.2.3. Mode of action of quinolones ............................................................................................. 23 1.2.4. Plasmid-mediated resistance ............................................................................................... 24 1.2.5. Chromosome-mediated resistance ..................................................................................... 25 1.2.6. Overcoming quinolone resistance ……..………………………………………….………..……….………25 1.3. Overview of ‘Trojan Horse’ strategy ........................................................................................... 26 1.3.1. Siderophore-fluoroquinolone conjugates ........................................................................... 29 1.3.2. Glycosylated-fluoroquinolones conjugates ......................................................................... 31 3 1.3.3. Peptide-drug conjugates ...................................................................................................... 33 1.3.4. Peptide-Trojan Horse conjugates ........................................................................................ 34 1.4. Peptide Transporters ................................................................................................................... 34 1.4.1. ABC transporters .................................................................................................................. 34 1.4.1.2. Substrate specificity ....................................................................................................... 35 1.4.2. Overview of POT family transporters .................................................................................. 36 1.4.2.2. Mode of action .............................................................................................................. 36 1.4.2.3. Selectivity mechanism ……..………………………………….………………………………………..….38 1.5. Biolabile linkers ........................................................................................................................... 39 1.5.1. Disulfide linkers.................................................................................................................... 39 1.5.1.2. Release of disulfide-based prodrugs ............................................................................. 41 1.6. Project overview .......................................................................................................................... 44 2. Results and discussion ...................................................................................................................... 46 2.1. Synthesis of Ala-Ala-ciprofloxacin conjugate 38 via non-biolabile amide .................................. 46 2.1.1. Methylation of cirpofloxacin................................................................................................ 46 2.1.2. Conjugation of Boc-Ala-Ala-OH to methyl-ciprofloxacin 41 ................................................ 48 2.1.3. Deprotection of conjugate 43 .............................................................................................. 49 2.1.4. Counter ion exchange .......................................................................................................... 51 2.2. Synthesis of ciprofloxacin-disulfide-Ala conjugate 39................................................................. 52 2.2.1. Disulfide conjugation ........................................................................................................... 54 2.2.1.1. Boc-protection of ciprofloxacin ..................................................................................... 56 2.2.1.2. Dicyclohexylcarbodiimide (DCC)-mediated esterification ........................................... 56 2.2.1.3. NHS/DCC-mediated esterification................................................................................. 58 2.2.1.4. HBTU and HATU –mediated esterification .................................................................... 61 2.2.2.Conjugation of alanine .......................................................................................................... 64 2.2.3. Deprotection of conjugate 57 .............................................................................................. 65 2.2.4. Counter ion exchange of 58 ................................................................................................. 66 2.3. Synthesis of ciprofloxacin-disulfide-diAla conjugate 40 ............................................................. 67 2.3.1. Conjugation of Boc-diAla 59 to Boc-ciprofloxacin-2,2’-dithiodiethanol 52 ......................... 68 4 2.3.2. Deprotection of
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