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Elucidation of Mechanisms of Antibiotic Subversion in Mycobacteria Elucidation of mechanisms of antibiotic subversion in mycobacteria Krupa Naran Division of Medical Microbiology Department of Clinical Laboratory Sciences University of Cape Town A thesis submitted to the Faculty of Health Sciences, University of Cape Town, in fulfilment of the requirements for the degree of Doctor of Philosophy. February 2015. The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgement of the source. The thesis is to be used for private study or non- commercial research purposes only. Published by the University of Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. University of Cape Town There was a beginning of time. There was a time before the beginning of time. There was a time before the time before the beginning of time. There is being. If there is being, there must be non-being. If there is non-being, There must have been a time when even non-being didn’t exist. Suddenly there was non-being. But can any non-being really exist, And can being not-exist? I just said something, But did what I just said really Say anything, or not? ―Chuang-tzu i Declaration I declare that this thesis is my own unaided work. It is being submitted for the degree of Doctor of Philosophy at the University of Cape Town. It has not been submitted for any degree or examination at any other university. Krupa Naran 16 February 2015 Date ii Abstract The intrinsic resistance of Mycobacterium tuberculosis (Mtb) to antibiotics is generally attributed to multiple factors, most significantly the low permeability of the mycobacterial cell wall, the operation of various drug inactivating systems, and the activity of efflux pumps. This study aimed to investigate the role of various components of the “intrinsic resistome” that limit the efficacy of antitubercular agents. The DNA damage response: the SOS response was hypothesized to play a role in antibiotic- mediated cellular death, and that disabling the mycobacterial SOS response, by generating non-cleavable LexA mutants (lexAInd-), could be used as a tool to validate antibiotic- mediated cell death. To this end, the M. smegmatis (Msm) cleavable LexA was shown to be essential for induced mutagenesis and damage tolerance and that an intact DNA damage repair system is required to respond to antibiotic-mediated DNA damage. In contrast, Mtb cleavable LexA was required for induced mutagenesis but not necessarily damage sensitivity. In addition, the Mtb SOS response does not contribute significantly to remediation of antibiotic-mediated DNA damage. Collectively, these data suggest that DNA repair mechanisms differ between the mycobacterial species and despite effectively inactivating the LexA-dependent DNA repair mechanism(s) in Msm and Mtb, these organisms are able to circumvent this pathway and successfully remediate damaged DNA sustained under various conditions. Furthermore, Mtb auto-bioluminescent reporter strains were generated by introducing the lux operon downstream of the recA or radA promoters. Analysis of a panel of antimicrobials against these strains allowed for the identification of true DNA-damaging agents and the evaluation of the kinetics of the DNA-damage response, in a concentration- and time-dependent manner. Efflux-mediated drug resistance: This study aimed to evaluate the interactions between pairwise combinations of selected antimicrobials and efflux pump inhibitors (EPIs), in vitro and ex vivo, and to identify a novel verapamil (VER)-analogue with improved efficacy against Mtb. Subsequently, a candidate EPI was identified, with equivalent in vitro synergistic effects to VER when used in combination with various antibiotics but with reduced cytotoxic effects, ex vivo, when compared to VER. iii Mycothiol-mediated protection: It was hypothesized that undetectable levels of mycothiol (MSH) in Mtb would potentiate the use of current antibiotics. To investigate the contribution of the cellular antioxidant, MSH, to the mitigation of antimicrobial efficacy, this study aimed to disrupt MSH production by conditionally knocking-down expression of the essential gene, mshC. The mshC knock-down mutants (in all configurations) were not anhydrotetracycline (ATC)-regulatable in liquid or on solid medium, which was subsequently validated with quantitative gene expression analysis. These data suggest that a tetracycline (Tet)-based conditional expression system may not be applicable to mshC. In conclusion, Mtb has a multitude of inherent mechanisms to subvert the effects of antimicrobial treatment. This study has contributed to the understanding of certain aspects of the intrinsic resistome and in doing so, established tools that can be used in future drug discovery programmes. iv Acknowledgements I am grateful for funding received from the Carnegie Corporation of New York, the German Academic Exchange Service (DAAD)/National Research Foundation (NRF), and the University of Cape Town (UCT). I wish to acknowledge AstraZeneca India for the 3-month exchange opportunity, funded by the WIPO Research Initiative, and Bioventures for Global Health (BVGH) and facilitated by the Medical Research Council (MRC). To my beloved parents, Harry and Meera, words alone cannot describe my gratitude to you both. I thank you for giving your children the freedom to dream, for all your sacrifices, understanding, unshakeable faith and enduring love. My journey is your journey, my achievements are yours. You are my heart. My brother, Ravi, through you I have learnt what it means to persevere and that no dream is unattainable. You are my hope. To Seema and Rajen, you’ve shown me that success is achievable through balance in life. You are my strength. My nieces, Rhea and Aaral, may I always live up to your standards. You are my moral compass. To my supervisor and mentor, Assoc. Prof. Digby Warner, you have taught me to go beyond my perceived capabilities and expectations and to make the unimaginable and impossible just another day in Wonderland. I thank you for adopting this once orphaned Master’s student, and for guiding, motivating and inspiring me. We are the reflection of those that have the greatest influence in our lives; I am grateful to you for your part. To my co-supervisor and mentor, Prof. Valerie Mizrahi, your astounding knowledge never fails to amaze and inspire me. I thank you for your unwavering guidance and support. You are and will be a role model for generations to come. To my colleagues at the MMRU, you are each special and worthy of every success that may come your way. I thank you all for your assistance, support and for making this a truly memorable experience. To our collaborator, Prof. Kelly Chibale, and colleagues from the UCT Department of Chemistry, I thank you for teaching me to “think like a chemist”. Our collaboration has shown me that the mind is pliable and it’s never too late to learn something new. v Publications from this thesis Li, Y., de Kock, C., Smith, P. J., Guzgay, H., Hendricks, D. T., Naran, K., Mizrahi, V., Warner, D. F., Chibale, K. and Smith, G. S. (2012). Synthesis, characterization, and pharmacological evaluation of silicon-containing aminoquinoline organometallic complexes as antiplasmodial, antitumor, and antimycobacterial agents. Organometallics 32(1): 141-150. Tukulula, M., Sharma, R.-K., Meurillon, M., Mahajan, A., Naran, K., Warner, D., Huang, J., Mekonnen, B. and Chibale, K. (2012). Synthesis and antiplasmodial and antimycobacterial evaluation of new nitroimidazole and nitroimidazooxazine derivatives. ACS medicinal chemistry letters 4(1): 128-131. Mjambili, F., Njoroge, M., Naran, K., De Kock, C., Smith, P. J., Mizrahi, V., Warner, D. and Chibale, K. (2014). Synthesis and biological evaluation of 2-aminothiazole derivatives as antimycobacterial and antiplasmodial agents. Bioorganic & medicinal chemistry letters 24(2): 560-564. Singh, K., Kumar, M., Pavadai, E., Naran, K., Warner, D. F., Ruminski, P. G. and Chibale, K. (2014). Synthesis of new verapamil analogues and their evaluation in combination with rifampicin against Mycobacterium tuberculosis and molecular docking studies in the binding site of efflux protein Rv1258c. Bioorganic & medicinal chemistry letters 24(14): 2985-2990. Naran, K., Singh, K., Kumar, M., Chibale, K. and Warner, D. F. (2015). Identification of a novel verapamil-analogue with improved in vitro and ex vivo profiles against Mycobacterium tuberculosis. In preparation. Naran, K., Ioerger, T.R., Wasuna, A., Chibale, K., Sacchettini, J.C. and Warner, D.F. (2015). Identification of a novel nitroimidazole with potent activity against Mycobacterium tuberculosis. In preparation. vi Table of Contents Declaration ...................................................................................................................... ii Abstract .......................................................................................................................... iii Acknowledgements .......................................................................................................... v Publications from this thesis ............................................................................................ vi List of Figures .................................................................................................................. xi List of Tables ................................................................................................................... xi Chapter 1: General Introduction ......................................................................................
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