Biography

Professor Fisher read Chemistry at University College, Oxford (1970-74) and from 1974-78 did his PhD in mechanistic enzymology at Harvard University supervised by Jeremy Knowles FRS. He did postdoctoral work (1978-81) on DNA gyrase with Marty Gellert at the National Institutes of Health in Bethesda funded by a Damon Runyon-Walter Winchell Cancer Fellowship and an NIH Visiting Fellowship. His work helped characterize a new E. coli topoisomerase (Gellert et al, 1979) and established that the unique DNA supercoiling activity of E. coli DNA gyrase occurs by the crossing of a DNA helix through a transient DNA break in a second helical segment (Mizuuchi et al, 1980; Fisher et al, 1981).

In 1981, he joined the Biophysics Department at King’s College London as a Cancer Research Campaign Return Fellow and Honorary Lecturer in Biophysics collaborating independently to identify a novel human immunoglobulin gene enhancer (Mills et al, 1983). In 1983, he moved to a Lectureship in Biochemistry at St George’s. He was promoted to Reader in Biochemistry in 1993 and to Professor of Molecular Biology in 1996.

Other activities

In previous senior roles at St George's, he was Deputy Principal (2017-2018), Dean of Research (2015-18) and Joint Foundation Director of the Cardiovascular and Cell Sciences Research Institute (2013-16).

From 1990-2001, he organised twelve annual DNA Topoisomerase in Therapy meetings in New York and Amsterdam and has spoken widely at recent Gordon Conferences and EMBO Workshops. He is a regular contributor to the annual ICARe course organized by the Institut Pasteur that aims to train the next generation of scientists, clinicians, regulators, pharmacologists and drug developers to combat antimicrobial drug resistance.

Professor Fisher has served in editorial roles for the Biochemical Journal and Bioscience Reports, and on the editorial boards of Antimicrobial Agents and Chemotherapy and the Journal of Antimicrobial Chemotherapy.        

The type II DNA topoisomerases are ubiquitous and essential enzymes that alter DNA topology to control DNA supercoiling and unlink catenated chromosomes prior to cell division. They act as ATP-driven clamps that capture a DNA duplex and pass it through a double-strand DNA break involving a DNA cleavage complex. Many important anti-infective and anticancer drugs work by trapping this complex (Yague et al), an event that is lethal to the cell. We are studying the cleavage complex and other topoisomerase intermediates as potential drug targets using a variety of approaches including molecular biology, microbiology, bacterial genetics, protein expression and structural biology.

Following on from my postdoctoral work at NIH with Marty Gellert that defined the double-strand break mechanism of Escherichia coli gyrase, our team has sought to address how topoisomerases act as ATP-dependent molecular machines and interact with drugs. Our group co-discovered the human topoisomerase IIbeta isoform (Austin and Fisher, Austin et al), cloned and characterised both alpha and beta isoforms (Wasserman et al; Austin et al; Sng et al; Capranico et al), as well as topo II from the fungal pathogen Candida albicans (Keller et al), and used expression in yeast to dissect function and drug inhibition (Patel et al). In complementary work, we have focused on bacterial gyrase and topo IV and were among the first groups to investigate these enzymes in medically relevant pathogens such as Streptococcus pneumoniae, Staphylococcus aureus and Mycobacterium tuberculosis (Pan et al; Sreedharan et al; Cambau et al; Aubry et al).

One major aim of our research has been to understand in detail the mode of action of fluoroquinolones, a clinically important group of antibacterials that target gyrase and topoisomerase IV. By cloning and sequencing an E. coli gyrase gene conferring quinolone resistance-the first from a clinical isolate (Cullen at al)- we could use a novel Hinf1-RFLP assay that we developed (Fisher et al; Sreedharan et al) , PCR and DNA sequencing (Oram and Fisher) to show that resistance commonly arises by mutations at two residues highly conserved between gyrase and topo IV and across different species. Further, we have shown that the bacterial target of particular quinolones in staphylococci and streptococci can be gyrase, topo IV or both (dual targeting)(Pan and Fisher; Alovero et al; Gould et al; Morris et al). We have proposed that dual targeting drugs are desirable in minimising the emergence of resistance (as two mutations are needed)(Pan and Fisher; Heaton et al), a property we established for gemifloxacin and besifloxacin that contributed to the FDA approval of these fluoroquinolones for pneumococcal pneumonia and bacterial conjunctivitis (Heaton et al; Cambau et al)

A key focus of current work is to determine the structures of intermediates in the topoisomerase reaction pathway. In collaboration with Mark Sanderson, we solved the first X-ray crystal structures of topo IV-DNA cleavage complexes with fluoroquinolones (Laponogov et al; Veselkov et al) and with the antibacterial quinazolinediones, a new inhibitor class active against quinolone-resistant strains (Pan et al; Laponogov et al). We found that two drug molecules are intercalated at the site of DNA cleavage anchored by specific contacts with the topo IV protein (Laponogov et al). These protein contacts differ for the quinazolinediones thus bypassing target resistance and setting a design precedent for new drugs that kill resistant bacteria (Skepper et al, Lapointe et al). We are using our recent structures of open and closed clamp topo IV intermediates (Laponogov et al 2013, 2018) to illuminate the molecular mechanisms of topoisomerases and realise their potential for new drug discovery.  

PUBLICATIONS:

Lapointe G, Skepper CK, Holder LM, Fisher LM, Selvarajah J, et al. (2021) Discovery and optimization of DNA gyrase and topoisomerase IV inhibitors with potent activity against fluoroquinolone-resistant gram-positive bacteria. J Med Chem 64: 6329-6357.

Skepper CK, Armstrong D, Balibar CJ, Fisher LM, Selvarajah J, et al. (2020) Topoisomerase inhibitors addressing fluoroquinolone resistance in Gram-negative bacteria. J Med Chem 63: 7773-7816.

Laponogov I, Pan XS, Veselkov DA, Skamrova GB, Umrekar T, Fisher LM, Sanderson MR (2018) Trapping of the transport-segment DNA by the ATPase domains of a type II topoisomerase. Nat Commun 8: 2579. *Recommended as a milestone paper in the field by the Faculty of 1000.

Veselkov DA, Laponogov I, Pan XS, Selvarajah J, Skamrova GB, Branstrom A, Narasimhan J, Vara Prasad JVN, Fisher LM, Sanderson MR (2016) Structure of a quinolone-stabilized cleavage complex of topoisomerase IV from Klebsiella pneumoniae and comparison with a related Streptococcus pneumoniae complex. Acta Crystallogr Part D Structural Biology 72: 488-496. Structure featured on the front cover of this issue.

Laponogov I, Veselkov DA, Pan XS, Cirz RT, Wagman AS, Moser H.E, Fisher LM, Sanderson MR (2016) Exploring the active site of the Streptococcus pneumoniae topoisomerase IV-DNA cleavage complex with novel 7,8-bridged fluoroquinolones. Open Biology 6 pii: 160157.

Arnoldi E, Pan XS, Fisher LM (2013) Functional determinants of gate-DNA selection and cleavage by bacterial type II topoisomerases. Nucleic Acids Res 41: 9411-9423.

Laponogov I, Veselkov DA, Crevel IM, Pan X-S, Fisher LM, Sanderson MR (2013) Structure of an ‘open’ clamp type II topoisomerase-DNA complex provides a mechanism for DNA capture and transport. Nucleic Acids Res 41: 9911-9923. *Recommended as a high impact paper by the Faculty of 1000.

Laponogov I, Pan XS, Veselkov DA, McAuley K, Fisher LM, Sanderson MR (2010) Structural basis of gate-DNA breakage and resealing by type II topoisomerases. PLoS ONE 5: e11338.

Laponogov I, Sohi MK, Veselkov DA, Pan XS, Sawhney R, Thompson AW, McAuley K, Fisher LM, Sanderson MR (2009) Structural insight into the quinolone-DNA cleavage complex of type IIA topoisomerases. Nature Struct Mol Biol 16: 667-669.

Pan XS, Gould KA, Fisher LM (2009) Probing the differential interactions of quinazolinedione PD 0305970 and quinolones with gyrase and topoisomerase IV. Antimicrob Agents Chemother 53: 3822-31.

Cambau E, Matrat S, Pan XS, Roth Di Bettoni R, Corbel C, Aubry A, Lascols C, Driot J-Y, Fisher LM (2009) Target specificity of the new fluoroquinolone besifloxacin in Streptococcus pneumoniae, Staphylococcus aureus and E. coli. J Antimicrob Chemother 63: 443-450.

Pan XS, Dias M, Palumbo M, Fisher LM (2008) Clerocidin selectively modifies the gyrase-DNA gate to induce irreversible and reversible DNA damage. Nucleic Acids Res 36: 5516-29.

Sohi MK, Veselkov DA, Laponogov I, Pan XS, Fisher LM, Sanderson MR (2008) The difficult case of crystallization and structure solution for the ParC55 breakage-reunion domain of topoisomerase IV from Streptococcus pneumoniae. PLoS ONE 3: e3201.

Fisher LM, Pan XS (2008) Methods to assay inhibitors of DNA gyrase and topoisomerase IV activities. Methods Mol Med 142: 11-23.

Richter SN, Giaretta G, Comuzzi V, Leo E, Mitchenall LA, Fisher LM, Maxwell A, Palumbo M (2007) Hot-spot consensus of fluoroquinolone-mediated DNA cleavage by Gram-negative and Gram-positive type II topoisomerases. Nucleic Acids Res 35: 6075-6085.

Laponogov I, Veselkov DA, Sohi MK, Pan XS, Achari A, Yang C, Ferrera JD, Fisher LM, Sanderson MR (2007) Breakage-reunion domain of Streptococcus pneumoniae topoisomerase IV: crystal structure of a gram-positive quinolone target. PLoS ONE 2: e301.

Richter SN, Leo E, Giarerra G, Gatto B, Fisher LM, Palumbo M (2006) Clerocidin interacts with the cleavage complex of Streptococcus pneumoniae topoisomerase IV to induce selective irreversible DNA damage. Nucleic Acids Res 34: 1982-1991.

Aubry A, Fisher LM, Jarlier V, Cambau E (2006) First functional characterisation of a singly-expressed bacterial type II topoisomerase: the enzyme from Mycobacterium tuberculosis. Biochem Biophys Res Comm 348: 158-165.

Sriram D, Aubry A, Yogeeswari P, Fisher LM (2006) Gatifloxacin derivatives: synthesis, activities and inhibition of Mycobacterium tuberculosis DNA gyrase. Bioorganic and Medicinal Chemistry Letters 16: 2982-2985.

Aubry A, Veziris N, Cambau E, Truffot-Pernot C, Jarlier V, Fisher LM (2006) Novel gyrase mutations in quinolone-resistant and -hypersusceptible clinical isolates of Mycobacterium tuberculosis: functional analysis of mutant enzymes. Antimicrob Agents Chemother 50: 104-112.

Leo E, Gould KA, Pan XS, Capranico G, Sanderson MR, Palumbo M and Fisher LM (2005) Novel symmetric and asymmetric DNA scission determinants for Streptococcus pneumoniae gyrase and topo IV are clustered at the DNA breakage site. J Biol Chem 280: 14252-14263.

Gould KA, Pan XS, Kerns RA, Fisher LM (2004) Ciprofloxacin dimers target gyrase in Streptococcus pneumoniae. Antimicrob Agents Chemother 48: 2108-2115.

Aubry A, Pan XS, Fisher LM, Cambau E (2004) Mycobacterium tuberculosis DNA gyrase: interaction with quinolones and correlation with drug activity in vivo. Antimicrob Agents Chemother 48: 1281-1288.

Fisher LM, Gould KA, Pan XS, Patel S, Heaton VJ (2003) Analysis of dual active fluoroquinolones in Streptococcus pneumoniae.J Antimicrob Chemother 52: 312-313.

Fisher LM, Heaton VJ (2003) Dual activity of fluoroquinolones against Streptococcus pneumoniae. J Antimicrob Chemother 51: 464-465.

Pan XS, Hamlyn PJ, Talens-Visconti R, Alovero FL, Manzo RH, Fisher LM (2002) Small colony mutants of Staphylococcus aureus allow selection of gyrase-mediated resistance to dual-target fluoroquinolones. Antimicrob Agents Chemother 46: 2498-2506.

Yague G, Morris JE, Pan XS, Gould KA, Fisher LM (2002) Cleavable complex formation by wild-type and quinolone-resistant Streptococcus pneumoniae type II topoisomerases mediated by gemifloxacin and other fluoroquinolones. Antimicrob Agents Chemother 46: 413-419.

Morris JE, Pan XS, Fisher LM (2002) Grepafloxacin, a dimethyl derivative of ciprofloxacin, targets gyrase in Streptococcus pneumoniae: role of the C-5 group in target specificity. Antimicrob Agents Chemother 46: 582-585.

Pan XS, Yague G, Fisher LM (2001) Quinolone resistance mutations in Streptococcus pneumoniae GyrA and ParC proteins: mechanistic insights into quinolone action from enzymatic analysis, intracellular levels and phenotypes of wild-type and mutant proteins. Antimicrob Agents Chemother 45: 3140-3147.

Sayer PJ, Goble ML, Oram M, Fisher LM (2001) Plasmid DNA supercoiling by DNA gyrase. Methods Mol Biol 95: 25-33.

Patel S, Jazrawi E, Creighton AM, Austin CA, Fisher LM (2000) Probing the interaction of the cytotoxic bisdioxopiperazine ICRF-193 with the closed clamp form of human topoisomerase IIalpha. Mol Pharmacol 58: 560-568.

Heaton VJ, Ambler JE, Fisher LM (2000) Potent antipneumococcal activity of gemifloxacin is associated with dual targeting of gyrase and topoisomerase IV, an in vivo target preference for gyrase, and enhanced stabilization of cleavable complexes in vitro. Antimicrob Agents Chemother 44: 3112-3117.

Patel S, Keller BA, Fisher LM (2000) Mutations at Arg486 and Glu571 in humantopoisomerase IIalpha confer resistance to amsacrine: relevance for antitumor drug resistance in human cells. Mol Pharmacol 57: 784-791.

Alovero FL, Pan XS, Morris JE, Manzo RH, Fisher LM (2000) Engineering the specificity of antibacterial fluoroquinolones: benzenesulfonamide modifications at C-7 of ciprofloxacin change its primary target in Streptococcus pneumoniae from topoisomerase IV to gyrase. Antimicrob Agents Chemother 44: 320-325.

Heaton VJ, Goldsmith CE, Ambler JE, Fisher LM (1999) Activity of gemifloxacin against penicillin- and ciprofloxacin-resistant Streptococcus pneumoniae displaying topoisomerase- and efflux-mediated resistance mechanisms. Antimicrob Agents Chemother 43: 2998-3000.

Pan XS, Fisher LM (1999) Streptococcus pneumoniae DNA gyrase and topoisomerase IV: overexpression, purification, and differential inhibition by fluoroquinolones. Antimicrob Agents Chemother 43: 1129-1136.

Sng JH, Heaton VJ, Bell M, Maini P, Austin CA, Fisher LM (1999) Molecular cloning and characterization of the human topoisomerase IIalpha and IIbeta genes: evidence for isoform evolution through gene duplication. Biochim Biophys Acta 1444: 395-406.

Pan XS, Fisher LM (1998) DNA gyrase and topoisomerase IV are dual targets of clinafloxacin action in Streptococcus pneumoniae. Antimicrob Agents Chemother 42: 2810-2816.

Binaschi M, Farinosi R, Austin CA, Fisher LM, Zunino F, Capranico G (1998) Human DNA topoisomerase IIalpha-dependent DNA cleavage and yeast cell killing by anthracycline analogues. Cancer Res 58: 1886-1892.

Cowell IG, Willmore E, Chalton D, Marsh KL Jazrawi E, Fisher LM, Austin CA (1998) Nuclear distribution of human topoisomerase IIbeta: a nuclear targeting signal resides in the 116-residue C-terminal tail. Exp Cell Res 243: 232-240.

Fisher LM, Capranico G, Austin CA (1998) Anticancer drug action on topoisomerase II: role of the ternary DNA complex in drug sensitivity and resistance, in ‘Cancer research supported under Biomed 1’, ed SS Baig, (IOS Press, Amsterdam) pp 164-110.

Fisher LM (1998) New insights into mechanisms of quinolone action and resistance. Infections in Medicine 15 (Supplement E): 55-60.

Patel S, Sprung AU, Keller BA, Heaton VJ, Fisher LM (1997) Identification of yeast DNA topoisomerase II mutants resistant to the anticancer drug doxorubicin: implications for the mechanisms of doxorubicin action and cytotoxicity. Mol Pharmacol 52: 658-666.

Keller BA, Patel S, Fisher LM (1997) Molecular cloning and expression of the Candida albicans TOP2 gene allows study of fungal DNA topoisomerase II inhibitors in yeast. Biochem J 324: 329-339.

Pan XS, Fisher LM (1997) Targeting of DNA gyrase in Streptococcus pneumoniae by sparfloxacin: selective targeting of gyrase or topoisomerase IV by quinolones. Antimicrob Agents Chemother 41: 471-474.

Meczes EL, Marsh KL, Fisher LM, Rogers MP, Austin CA (1997) Complementation of temperature-sensitive topoisomerase II mutations in Saccharomyces cerevisiae by a human TOP2beta construct allows the study of topoisomerase IIbeta inhibitors in yeast. Cancer Chemother Pharmacol 39: 367-375.

Cornarotti M, Tinelli S, Willmore E, Zunino F, Fisher LM, Austin CA, Capranico G (1996) Drug sensitivity and sequence specificity of human recombinant DNA topoisomerases IIalpha (p170) and IIbeta (p180). Mol Pharmacol 50: 1463-1471.

Marsh KL, Willmore E, Tinelli S, Cornarotti M, Meczes E, Capranico G, Fisher LM, Austin CA (1996) Amsacrine-promoted DNA cleavage site determinants for the two human DNA topoisomerase II isoforms, alpha and beta. Biochem Pharmacol 52: 1675-1685.

Pan XS, Ambler J, Mehtar S, Fisher LM (1996) Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Antimicrob Agents Chemother 40: 2321-2326.

Pan XS, Fisher LM (1996) Cloning and characterization of the parC and parE genes of Streptococcus pneumoniae encoding DNA topoisomerase IV: role in fluoroquinolone resistance. J Bacteriol 178: 4060-4069.

Sun L, Sreedharan S, Plummer K, Fisher LM (1996) NorA plasmid resistance to fluoroquinolones: role of copy number and norA frameshift mutations. Antimicrob Agents Chemother 40: 1665-1669.

Oram M, Dosanjh B, Gormley NA, Smith CV, Fisher LM, Maxwell A, Duncan K (1996) The mode of action of GR122222X, a novel inhibitor of bacterial DNA gyrase. Antimicrob Agents Chemother 40: 473-476.

Austin CA, Marsh KL, Wasserman RA, Willmore E, Sayer PJ, Wang JC, Fisher LM (1995) Expression, domain structure and enzymatic properties of an active recombinant human DNA topoisomerase II beta. J Biol Chem 270: 15739-15746.

Li MS, Sun L, Satoh T, Fisher LM, Spry CSJ (1995) Human eosinophil major basic protein, a mediator of allergic inflammation is expressed by alternate splicing from two promoters. Biochem J 305: 921-927.

Sun L, Li MS, Fisher LM, Spry CSJ (1995) Expression in Escherichia coli and purification of human eosinophil-derived neurotoxin with ribonuclease activity. Protein Expression and Purification 6: 685-692.

Alonso JC, Fisher LM (1995) Nucleotide sequence of the Staphylococcus aureus recF gene cluster and complementation in Bacillus subtilis recF mutants. Mol Gen Genet 246: 680-686.

Wasserman RA, Austin CA, Fisher LM, Wang JC (1993) The use of yeast in the study of anticancer drugs targeting DNA topoisomerases: expression of a functional recombinant human DNA topoisomerase IIalpha in yeast. Cancer Res 53: 3591-3596.

Austin CA, Sng JH, Patel S, Fisher LM (1993) Novel HeLa topoisomerase II is the IIbeta isoform: complete coding sequence and homology with other type II topoisomerases. Biochim Biophys Acta 1172: 283-291.

Patel S, Fisher LM (1993) Novel selection and genetic characterisation of an etoposide-resistant human leukaemic CCRF-CEM cell line. Brit J Cancer 67: 456-463.

Fisher LM, Oram M, Sreedharan S (1992) DNA gyrase: mechanism and resistance to 4-quinolone antibacterial agents in ‘Molecular Biology of DNA Topoisomerases and its Application to Chemotherapy’ ed. T. Andoh, CRC Press, Boca Raton, pp 139-142.

Capranico G, Tinelli S, Austin CA, Fisher LM, Zunino F (1992) Different patterns of gene expression of topoisomerase II isoforms in differentiated tissues during murine development. Biochim Biophys Acta 1132: 43-48.

Oram M, Fisher LM (1992) Escherichia coli DNA gyrase: genetic analysis of gyrA and gyrB mutations responsible for thermosensitive enzyme activity. FEBS Letters 312: 61-65.

Oram M, Fisher LM (1992) Escherichia coli DNA topoisomerase I mutant has a compensatory mutation that alters two residues between functional domains of DNA gyrase A protein. J Bacteriol 174: 4175-4178.

Austin CA, Patel S, Ono K, Nakane H, Fisher LM (1992) Site-specific cleavage by mammalian DNA topoisomerase II induced by novel flavone and catechin derivatives. Biochem J 282: 883-889.

Margerrison EEC, Hopewell R, Fisher LM (1992) Nucleotide sequence of the Staphylococcus aureus gyrB-gyrA locus encoding the DNA gyrase A and B proteins. J Bacteriol 174: 1596-1603.

Fisher LM, Austin CA, Hopewell R, Margerrison EEC, Oram M, Patel S, Plummer K, Sng JH, Sreedharan S (1992) DNA supercoiling and relaxation by ATP-dependent DNA Topoisomerases. Phil Trans Royal Society Lond B 336: 83-91.

Oram M, Fisher LM (1991) 4-quinolone resistance mutations in the DNA gyrase of Escherichia coli clinical isolates identified using the polymerase chain reaction. Antimicrob. Agents Chemother 35: 387-389.

Fasching CE, Tenover FC, Slama TG, Fisher LM, Sreedharan S, Oram M, Willard K, Sinn LM, Gerding DN, Peterson LR (1991) GyrA mutations in ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus from Indiana, Minnesota and Tennessee. J Infect Dis 164: 976-979.

Sreedharan S, Peterson LR, Fisher LM (1991) Ciprofloxacin resistance in coagulase-positive and -negative Staphylococci: role of mutations at Ser-84 in the DNA gyrase A protein of Staphylococcus aureus and Staphylococcus epidermidis. Antimicrob Agents Chemother 35: 2151-2154.

Austin CA, Fisher LM (1990) Isolation and characterisation of a human cDNA clone encoding a novel DNA topoisomerase II homologue from HeLa cells. FEBS Letters 266: 115-117.

Austin CA, Barot HA, Margerrison EEC, Turcatti G, Wingfield P, Hayes MV, Fisher LM (1990) Structure and partial amino acid sequence of calf thymus topoisomerase II: comparison with other type II enzymes. Biochem Biophys Res Comm 170: 763-768.

Austin CA, Fisher LM (1990) DNA topoisomerases: enzymes that change the shape of DNA. Science Progress 74: 147-161.

Patel S, Austin CA, Fisher LM (1990) Development and properties of an etoposide-resistant human leukaemic CCRF-CEM cell line. Anti-Cancer Drug Design 5: 149-157.

Sreedharan S, Oram M, Jensen B, Peterson LR, Fisher LM (1990) DNA gyrase gyrA mutations in ciprofloxacin-resistant strains of Staphylococcus aureus: close similarity with quinolone resistance mutations in Escherichia coli. J Bacteriol 172: 7260-7262.

Fisher LM, Hopewell R, Oram M, Sreedharan S (1990) Molecular basis of quinolone action and resistance, pp 177-190 In ‘Frontiers in Infectious Diseases: New Antimicrobial Strategies’ ed. H.C. Neu, Churchill Livingston.

Hopewell R, Oram M, Briesewitz R, Fisher LM (1990) DNA cloning and organisation of the Staphylococcus aureus gyrA and gyrB genes: close homology among gyrase proteins and implications for 4-quinolone action and resistance. J Bacteriol 172: 3481-3484.

Kuroda R, Takahashi E, Austin CA, Fisher LM (1990) DNA binding and intercalation by novel porphyrins: role of charge and substituents probed by DNase I footprinting and topoisomerase I unwinding. FEBS Letters 262: 293-298.

Fisher LM , Lawrence J, Josty I, Hopewell R, Margerrison EEC, Cullen ME (1989) Ciprofloxacin and the new fluoroquinolones: new concepts on the mechanism of action and resistance. American J Medicine 87: 5A:2S-8S.

Cullen ME, Wyke AW, McEachern F, Austin CA, Fisher LM (1989) Inhibition of DNA gyrase: bacterial sensitivity and clinical resistance to 4-quinolones, in Current Topics in Infectious Diseases and Clinical Microbiology 2: 41-47.

Austin CA, Barot HA, Margerrison EEC, Hayes MV, Fisher LM (1989) Biochemical and immunological characterisation of mammalian DNA topoisomerase II. Biochem Soc Trans 17: 528-529.

McEachern F, Fisher LM (1989) Regulation of DNA supercoiling in Escherichia coli: genetic basis of a compensatory mutation in DNA gyrase. FEBS Letters 253: 67-70.

Cullen ME, Wyke AW, Kuroda R, Fisher LM (1989) Cloning and characterisation of a DNA gyrase A gene from Escherichia coli that confers clinical resistance to 4-quinolones. Antimicrob Agents Chemother 33: 886-894.

Fisher LM (1987) DNA gyrase and the mode of action of 4-quinolone antibacterial agents. Fortschritte der antimikrobiellen und antineoplastischen chemotherapie. Band 6-19: 1585-1595.

Fisher LM, Barot HA, Cullen ME (1986) DNA gyrase complex with DNA: determinants for site-specific DNA breakage. EMBO J 5: 1411-1418.

Fisher LM, Belasco JG, Bruice TW, Albery WJ, Knowles JR (1986) Proline racemase: oversaturation and interconversion of enzyme forms., in Mechanisms of enzyme reactions: stereochemistry, ed. P. Frey, pp 205-216.

Belasco JG, Bruice TW, Fisher LM, Albery WJ, Knowles JR (1986) Energetics of proline racemase: rates, fractionation factors, and buffer catalysis in the oversaturated region. Nature of the interconversion of the two forms of free enzyme. Biochemistry 25: 2564-2571.

Fisher LM, Belasco JG, Albery WJ, Knowles JR (1986) Energetics of proline racemase: transition state fractionation factors for the two protons involved in the catalytic steps. Biochemistry 25: 2543-2551.

Fisher LM, Albery WJ, Knowles JR (1986) Energetics of proline racemase: tracer perturbation experiments that measure the interconversion rate of the two forms of free enzyme. Biochemistry 25: 2538-2542.

Fisher LM, Albery WJ, Knowles JR (1986) Energetics of proline racemase: racemization of unlabeled proline in the unsaturated, saturated and oversaturated regimes. Biochemistry 25: 2529-2537.

Fisher LM, Barot HA, Cullen ME, Hulton CSJ (1986) DNA breakage by Escherichia coli DNA gyrase in vitro and in vivo. Biochem Soc Trans. IBBG Symposium on DNA topoisomerase inhibitors as antimicrobial agents 14: 493-496.

Fisher LM, Kuroda R, Sakai TT (1985) Interaction of bleomycin A₂ with DNA: DNA unwinding and inhibition of bleomycin-induced DNA breakage by cationic thiazole amides related to bleomycin A₂. Biochemistry 24: 3199-3207.

Fisher LM (1984) DNA supercoiling and gene expression. Nature 307: 686-687.

Mills FC, Fisher LM, Kuroda R, Ford AM, Gould HJ (1983) DNase I hypersensitive sites in the chromatin of human mu immunoglobulin heavy chain genes. Nature 306: 809-812.

Fisher LM (1982) DNA unwinding in transcription and recombination. Nature 299: 105-106.

Fisher LM (1981) DNA supercoiling by DNA gyrase. Nature 299: 607-608.

Fisher LM, Mizuuchi K, O’Dea MH, Ohmori H, Gellert M (1981) Site-specific interaction of DNA gyrase with DNA. Proc Natl Acad Sci. USA 78: 4165-4169.

Gellert M, Fisher LM, Ohmori H, O’Dea MH, Mizuuchi K (1980) DNA gyrase: site-specific interactions and transient double strand DNA breakage of DNA. Cold Spring Harbor Symp Quant Biol XLV: 391-398.

Mizuuchi K, Fisher LM, O’Dea MH, Gellert M (1980) DNA gyrase action involves the introduction of transient double strand breaks into DNA. Proc Natl Acad Sci USA 77: 1847-1851.

Gellert M, Fisher LM, O’Dea MH (1979) DNA gyrase: purification and catalytic properties of a fragment of DNA gyrase B protein. Proc Natl Acad Sci USA 76: 6289-6293.

Fisher LM, Albery WJ, Knowles JR (1976) Energetics of triosephosphate isomerase:the nature of the proton transfer between the catalytic base and solvent water. Biochemistry 15: 5621-5626.

Fisher LM, Albery WJ, Knowles JR (1975) The nature of the proton transfer from an acid group at the active site of an enzyme, to solvent water. Symp Faraday Soc 10: 154-159.

Fisher LM (1979) The energetics of enzyme-catalysed proton transfer. Part 1: proline racemase; Part 2: triosephosphate isomerase. Ph D thesis, Harvard University.

Recent grants:

MRC MR/T00848/1 ‘Understanding DNA transport by topo IV and gyrase to counter antimicrobial resistance’. Fisher LM (PI) and Sanderson MR. 2019-2023. £848K.

BBSRC BB/K010069/1 ‘Molecular basis of DNA gating by topo IV and gyrase and its inhibition by antimicrobial drugs. Fisher LM (PI) and Sanderson MR. 2012-15. £640K.

Wellcome Trust-Seeding Drug Discovery (with Pharma) Fisher LM & Sanderson MR. £137K.

Novartis. ‘Biochemical and structural studies of bacterial topoisomerase-drug complexes’. Fisher LM jointly with Dr Mark Sanderson 2014-15. $200K.

BBSRC BB/H00405X/1 ’Mechanistic and structural analysis of topo IV and gyrase and their targeting by antibacterial quinolones’ Fisher LM (PI) and Sanderson MR 2009-12. £620K.

BBSRC BB/D01882X1 ‘Molecular characterisation of the FtsK DNA motor and its interactions with topo IV in chromosome segregation’ Fisher LM (PI) 2005-2008. £340K.

BBSRC BB/D0144841 ‘Recognition, opening and stabilization of DNA gates by topo IV, the chromosome decatenase’. Fisher LM (PI) 2005-2008. £240K.

BBSRC C16747 'Molecular characterisation of S. pneumoniae topoisomerase IV and gyrase complexes and their interactions with quinolones'. Fisher LM and Sanderson MR 2002-2005. £340K.

Earlier funding to L M Fisher (all as PI) from Cancer Research UK (eleven 3-year project grants), from the European Commission, and many project grants from pharmaceutical companies including Bausch and Lomb, Bayer, Glaxo, Novartis, Pfizer, PTC Therapeutics, and SmithKline Beecham.

In recent years, our main collaborations have been with:

Dr Mark Sanderson, Randall Centre for Cell and Molecular Biophysics, King’s College, London

Prof Manlio Palumbo, University of Padua, Italy

Dr Alexandra Aubry, University of Paris, France

Prof Emmanuelle Cambau, University of Paris, France.

Prof Caroline Austin, Biosciences Institute, Newcastle University, UK

Dr Art Branstrom, PTC Therapeutics, South Plainfield, NJ, USA

Dr Heinz Moser, Dr Colin Skepper and Dr Guillaume Lapointe, Novartis Institutes for Biomedical Research, Emeryville, USA.

Dr Aravindan Ilangovan, Queen Mary, University of London, UK

Professor Fisher contributes lectures and tutorials to undergraduate and postgraduate courses at St George's including the MBBS Introduction to Medicine, M Pharm Human Body module, the Translational Medicine MSc and several modules in the Biomedical Sciences BSc including the Fundamentals of the Living Cell, Genes and Gene Expression, and the Biology of Cancer, a module he originally set up. He is very active as a Personal Tutor to MBBS and Biomedical Sciences BSc students.

He has supervised 16 PhD students to completion. Four of his postdoctoral fellows have been appointed to professorships in the UK, France and Spain and other group members have held senior positions in pharmaceutical companies such as Pfizer and AstraZeneca.