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Inhibition of Class a and C Β-Lactamases

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INHIBITION OF CLASS A AND C β-LACTAMASES: CHALLENGES AND PROMISE by SARAH MICHEL DRAWZ Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Thesis Adviser: Robert A. Bonomo, M.D. Department of Pathology CASE WESTERN RESERVE UNIVERSITY May 2010 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ______________________________________________________ candidate for the Ph.D. degree *. (signed)_______________________________________________ (chair of the committee) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. TABLE OF CONTENTS TABLE OF CONTENTS 1 LIST OF TABLES 3 LIST OF FIGURES 5 ACKNOWLEDGEMENTS 8 LIST OF ABBREVIATIONS 9 ABSTRACT 10 CHAPTER 1 - Introduction Overview 12 Mechanism of Action of β-Lactam Antibiotics 13 Resistance to β-Lactam Antibiotics 14 -Lactamases 16 Circumventing β-Lactamases 28 β-Lactamase Inhibitors in Clinical Practice 30 Inhibitor-Resistant Class A β-Lactamases 39 The Promise of Novel β-Lactamase Inhibitors 50 Inhibition of Metallo-β-Lactamases 76 Tables 78 Figures 82 CHAPTER 2 - The Role of SHV Asn276 in Clavulanate Resistance Introduction 94 Materials and Methods 97 Results 103 Discussion 107 Conclusion 114 Tables 116 Figures 121 CHAPTER 3 - Inhibition of ADC by Boronates and Carbapenems Introduction 126 Materials and Methods 128 Results 135 Discussion 141 Conclusion 148 Tables 150 Figures 153 CHAPTER 4 - Catalytic and Inhibitory Properties of the Pseudomonas aeruginosa AmpC: Implications for an Inhibitor-Resistant Phenotype Introduction 167 1 Materials and Methods 169 Results 181 Discussion 190 Conclusion 205 Tables 206 Figures 216 CHAPTER 5 - Summary, Future Directions, and Lessons Learned Chapter 2 Summary 222 Chapter 2 Future Directions 223 Chapter 3 Summary 225 Chapter 3 Future Directions 226 Chapter 4 Summary 227 Chapter 4 Future Directions 228 Lessons Learned 230 A Perspective 234 Table 236 APPENDIX A – Molecular Modeling Terms 237 APPENDIX B – Penicillin Sulfone Inhibitors of Class D β-Lactamases 238 REFERENCES 271 2 LIST OF TABLES 1-1. Comparison of Ambler and Bush-Jacoby-Medeiros -lactamase 77 classification schemes 1-2. Kinetic properties of representative -lactamases 78 1-3. Kinetic properties of representative class A inhibitor-resistant enzymes 79 1-4. Kinetic properties of select inhibitors against different -lactamase 80 Ambler classes 2-1. MIC values (μg/ml) of E. coli DH10B expressing SHV-1 and Asn276 115 variants 2-2. Kinetic properties of SHV-1 and Asn276Asp for ampicillin, piperacillin, 116 nitrocefin, and cephalothin 2-3. Kinetic properties of SHV-1 and Asn276Asp for clavulanate, cephalothin 117 boronic acid derivatives, methylidene penem, and meropenem 2-4. Ratio of kcat/Km for IR to wild-type TEM and SHV enzymes 118 2-5. Ratio of kinact/Ki for IR to wild-type TEM and SHV enzymes 119 3-1. Ki and Ki appss of inhibitors in direct competition assays with ADC 149 3-2. ESI-MS analysis (amu) of ADC alone and incubated with inhibitors 150 3-3. MIC values (μg/ml) of ceftazidime and ceftazidime in combination with 4 151 μg/ml of boronic acid cephalothin analogs 4-1. Bacterial strains used in Chapter 4 studies 206 4-2. Primers used for cloning and mutagenesis in Chapter 4 207 4-3. MIC values (μg/ml) of P. aeruginosa strains PAO1 and 18SH, expressing 208 PDC-1 and PDC-3 β-lactamases, respectively 4-4. PDC-3 -lactamase substrate kinetics 209 4-5. Ki and Ki appss of inhibitors in direct competition assays with PDC-3 - 210 lactamase and NCF 4-6. kinact rates of inhibitors screened in Chapter 4 212 4-7. ESI-MS analysis (amu) of PDC-3 alone and incubated with inhibitors for 213 15 min at an I:E of 25:1 for boronate and 20:1 for PSR-3-283a and BAL29880. 3 4-8. Cefotaxime MICs (g/ml) of P. aeruginosa 18SH and PAO1 expressing 214 PDC-1 and PDC-3 β-lactamases, respectively, and E. coli DH10B expressing blaPDC-3 or blaPAO1 in pBC SK (-), inhibitors at 4 g/ml 4-9. MIC values (μg/ml) of P. aeruginosa 18SH and E. coli DH10B expressing 215 blaPDC-3 or blaPDC-3 variants at possible carboxylate binding sites. Inhibitors combined with 50 μg/ml ampicillin 5-1. Experiments planned or in progress for Pseudomonal AmpC 236 4 LIST OF FIGURES 1-1. Chemical structures of: (1) a penicillin; (2) a third-generation 81 cephalosporin; (3) a monobactam; (4-7) carbapenems; and (8-10) β- lactamase inhibitors in clinical practice. The numbering scheme for penicillins, cephalosporins, and monobactams is shown. Chemical structures of β-lactamase inhibitors in development: (11-14) monobactam derivatives; (15) a penicillin derivative; (16-20) penems; (21-23) penicillin sulfones; (24) a cephalosporin sulfone; (25) a boronic acid cephalothin analog; (26-29) non-β-lactams. 1-2. “Family portrait” of β-lactamase enzymes: (A) Class A, SHV-1; (B) 83 Class B, IMP-1; (C) Class C, E. coli AmpC; and (D) Class D, OXA-1 1-3. Proposed reaction mechanism for a penicillin β-lactam substrate by a 84 class A serine β-lactamase enzyme in which Glu166 participates in activating a water molecule for both acylation and deacylation. 1-4. Schmeatic representation of the Zn2+-binding site of a dinuclear subclass 85 B1 metallo--lactamase, such as B. cereus BcII 1-5. Proposed mechanism of inhibition for class A β-lactamases by 86 clavulanate showing the different acyl-enzyme fragmentation products (expressed in amu) that have been experimentally observed 1-6. Tautomers of imipenem hypothesized to form after acylation of 87 carbapenems by serine β-lactamases 1-7. Molecular representation of SHV-1-meropenem acyl-enzyme 88 1-8. Molecular representation of TEM-1 active site showing residues that are 89 most frequently implicated in the development of inhibitor-resistant TEM enzymes 1-9. Representation of proposed Henri-Michaelis preacylation complex of 90 TEM-1 and clavulanate 1-10. Proposed reaction mechanisms for the inactivation of a serine β- 91 lactamase by: (A) BRL 42715 showing formation of the seven-membered thiazepine ring; and (B) LN-1-255 showing intermolecular capture by the pyridyl nitrogen leading to a bicyclic aromatic intermediate 1-11. Molecular representation of cross-linked active site residues Ser64 and 92 Lys315 formed after aminolysis of O-aryloxycarbonyl hydroxamate inhibitor in E. cloacae P99 -lactamase 2-1. Chemical structures of compounds tested in Chapter 2 120 5 2-2. Immunoblot of E. coli DH10B expressing SHV-1, SHV Arg244Ser 121 variant, and Asn276 variants probed with SHV-1 polyclonal antibody 2-3. Deconvoluted ESI-MS spectra of: (A) SHV-1; and (B) SHV Asn276Asp 122 before and after 15 min inactivation with clavulanate at inhibitor:enzyme ratio of 1000:1 2-4. Molecular representation of SHV Asn276Asp based on SHV-1 showing 123 the increased interaction between Arg244 and 276Asp 2-5. Proposed reaction mechanism for inactivation of SHV-1 by clavulanate 124 3-1. Schemes illustrating the interactions of a serine β-lactamase with: (A) the 152 β- lactam cephalosporin ceftazidime; (B) the boronic acid ceftazidime analog, compound 2; and (C) the carbapenem imipenem 3-2. Chemical structures of: (A) commercially available inhibitors and 153 cephalosporin substrate cephalothin; (B) boronic acid derivatives; and (C) carbapenems used in Chapter 3 3-3. Overlay of the molecular coordinates for the E. coli AmpC covalently 154 bound to cephalothin substrate and boronic acid chiral cephalothin analog 3-4. Deconvoluted mass spectra of: (A) ADC β–lactamase alone; (B) ADC 155 after 15 min incubation with compounds 2 and 5; and (C) ADC β- lactamase after 15 min incubation with imipenem, ertapenem, doripenem, and meropenem 3-5. Proposed mechanism of the retroaldolic reaction leading to elimination of 157 C6 hydroxethyl substituent from the -lactamase: carbapenem acyl- enzyme 3-6. Discovery Studio multiple sequence protein alignment of crystal structure 158 coordinates for E. cloacae P99, E. coli AmpC, and E. coli CMY-2, and molecular models of PDC and ADC 3-7. Overlay of molecular coordinates for the E. coli AmpC-5 complex and 160 generated ADC-5 model colored by atom 3-8. Comparison of the binding site interactions between E. coli AmpC-5 (left 161 panel) and ADC-5 (right panel) 3-9. Molecular representation of: (A) ADC-imipenem acyl-enzyme model; 163 and (B) ADC-meropenem acyl-enzyme model 4-1. Chemical structures of: (A) β-lactam substrates; and (B) investigational 216 inhibitors tested in Chapter 4 4-2. Specific activity (M NCF hydrolyzed/sec/g protein) of crude protein 217 extract from P. aeruginosa PAO1 and 18SH without and following 3 hr 6 incubation with 50 µg/ml cefoxitin 4-3. Immunoblots of: (A) purified PDC-3 protein; and (B) purified β- 218 lactamase proteins from all Ambler classes and crude lysates of clinical strains 4-4. Proposed reaction intermediates detected on ESI-MS after 15 min 219 incubation of: (A) PSR-3-283a; and (B) BAL29880 with PDC-3 at an I:E -2 of 20:1. (C) Possible mechanism for elimination of the SO3 group from BAL29880 4-5. Structure of C6 α-hydroxymethyl penicillanate studied by Mobashery and 220 colleagues 4-6. Solvent-accessible surfaces of E. coli AmpC bound to the chiral 221 cephalothin analog boronate, compound 4c, and P. aeruginosa PDC-3 with the same inhibitor 7 ACKNOWLEDGEMENTS Many people have helped me complete this project. In particular, I thank my thesis committee for their time and attention to my academic development, and the members of the Bonomo lab for support and scientific guidance. My husband, Paul, has been my strongest source of support through these experiences. The encouragement from my parents has also been instrumental.
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