Professor Andrew Lovering

Professor Andrew Lovering

School of Biosciences
Professor of Structural Biology

Contact details

Telephone
+44 (0)121 41 45419
Email
a.lovering@bham.ac.uk
Address
704, School of Biosciences
The University 麻豆精选
Edgbaston
Birmingham
B15 2TT
United Kingdom

I am a Professor of Structural Biology here at Birmingham, and my research interests involve utilising structural biology (and complementary techniques) to investigate protein function – many of these projects involve the unusual predatory bacterium Bdellovibrio; see “Research” tab and be enthused!

Here is a link to a presentation given at an EMBO meeting that provides some examples of the kind of projects undertaken in the lab:  

Bacterial predators are fascinating organisms that may find general usage as “living antibacterials”. Our lab is chiefly concerned with understanding the tools they use to kill other bacteria and how they regulate the various stages of their unusual lifecycle. Approximately a third of the genome from the model predator Bdellovibrio bacteriovorus encodes for proteins with no discernable homology to those from other (non-predatory) bacteria; this makes structural methods ideal for investigating function. We study these predatory enzymes and protein complexes in-vitro, collaborating with Liz Sockett’s group in Nottingham to tie function in with in-vivo context.

The figure below demonstrates the staged lifecycle of Bdellovibrio, annotated with a select few of the structures we have solved.

lovering-webpage-figure2 

We take on a variety of projects, but typical areas include:

Invasion – how are prey cells recognized, and how do predators breach the outer membrane? This is a multifactorial process – no genetic resistance to predation has ever been observed (in contrast to bacteriophages and their receptors, which are subject to a relatively rapid development of resistance).

Protection – what factors prevent Bdellovibrio from killing itself? We published the first such example of a predator self-immunity protein in 2015 (an interesting case of evolution shaping one protein to block two enzymes): Nature Commun. 2015 Dec 2;6:8884.

Signalling – what are the stimuli that govern switching between the different lifecycle stages (swim > recognition > adhere > enter > metabolize > divide > exit)? Some of these pathways utilize the second messenger cyclic-di-GMP  (common to many bacteria, but used herein to regulate predation).

Metabolism – predators are very distinct, often losing pathways for amino acid and vitamin biosynthesis, but encoding a massive array of novel proteases, lipases, nucleases and transporters.

Motility – prey density is high in biofilms; predators can exploit this by using a cryptic form of motility (“smooth gliding” – that pushes the cell over surfaces, utilizing a motor that runs on a helical thread around the cell periphery).

Biography

I grew up in Wales (Barry to be precise) and studied for both my undergraduate degree (Biochemistry) and PhD (structural biology of therapeutic enzymes) at the University 麻豆精选, before beginning a 6 and a half year stint in Vancouver Canada. In my postdoctoral years I began to appreciate bacteria and the amazing diversity of mechanisms they utilize. In 2010 I came back to the UK to start my own group looking into how we can utilise a “living antibiotic”, the bacterium Bdellovibrio bacteriovorus, to tackle bacterial pathogens.

Recognition of our work has come from :
(2012) Presented with the ICAAC Young Microbiologist of the Year Award, administered by the American Society for Microbiology.
(2014-2017) Awarded prestigious EMBO Young Investigator status.
(2018-2023) Awarded Wellcome Investigator status.

Teaching

I teach on several undergraduate and postgraduate modules, including Bio311 (antibiotic resistance component) and Bio305 (cell wall biosynthesis and staphylococcal & streptococcal disease topics).

Postgraduate supervision

UK students can apply via the MIBTP scheme, and non-UK students by the Darwin scheme – both normally take applications at the end of the calendar year for entry the following year, please email me if you have any questions.

Research

Research Theme within School of Biosciences: Molecular Microbiology

X-Ray crystallography and structure: function relationships of bacterial proteins

My laboratory uses X-ray crystallography to study the molecular basis of protein function. We are interested in a variety of bacterial systems - especially those with the potential for antibiotic development. One of these systems involves analysis of the remarkable predatory bacterium Bdellovibrio bacteriovorus (in collaboration with Professor Liz Sockett at Nottingham). Predatory bacteria feed off and eventually kill other bacteria, and thus research into this process has potential therapeutic possibilities. Bdellovibrio is the model predatory organism, and possesses an unusual lifestyle where it enters its prey through the outer membrane and resides in the periplasm. The host cell changes shape (forming a structure termed the "bdelloplast") and the Bdellovibrio cell grows and replicates using material obtained from prey breakdown. Progeny then exit the dead host to start the cycle anew. Host-independent forms of Bdellovibrio may be grown separate from prey in rich media.

We are using X-ray crystallography to study Bdellovibrio proteins with the aim of understanding:

  • the precise function of proteins involved in predation events
  • how Bdellovibrio responds to the challenges of intraperiplasmic growth
  • what specifically regulates the alteration to a host-independent (non-predatory) lifestyle

Many of these proteins are unique to Bdellovibrio, and are thus termed part of the "predatosome". Of course, there is much more to study, not forgetting prey recognition events, membrane entry, bdelloplast formation, host material hydrolysis, predation on biofilms, and signalling/regulation of all of the above!

Reviews on this topic are included in the references below and short summaries can be found at .

The laboratory has a number of other collaborations and projects ongoing, both within and external to Birmingham.

Bdellovibrio predation lifecycle

Figure 1: Bdellovibrio predation lifecycle

Other activities

The lion’s share of my free time is taken up by my young family; outside this I favour sleep. Outside that, I like reading the Observer (disclaimer: other newspapers are available), watching sport, daydreaming, cooking & the great outdoors. Microbrew beer is welcome at any point and my lab like to visit the Birmingham Beer Festival each year for scientific discourse in the company of real ale.

Publications

Tyson J, Radford P, Lambert C, Till R, Huwiler SG, Lovering AL, Elizabeth Sockett R. Prey killing without invasion by Bdellovibrio bacteriovorus defective for a MIDAS-family adhesin. Nat Commun. 2024 Apr 9;15(1):3078. doi: 10.1038/s41467-024-47412-3.

Cooper BF, Ratkevičiūtė G, Clifton LA, Johnston H, Holyfield R, Hardy DJ, Caulton SG, Chatterton W, Sridhar P, Wotherspoon P, Hughes GW, Hall SC, Lovering AL, Knowles TJ. An octameric PqiC toroid stabilises the outer-membrane interaction of the PqiABC transport system. EMBO Rep. 2024 Jan;25(1):82-101

Caulton SG, Lambert C, Tyson J, Radford P, Al-Bayati A, Greenwood S, Banks EJ, Clark C,  Till R, Pires E, Sockett RE, Lovering AL. Bdellovibrio bacteriovorus uses chimeric fibre proteins to recognize and invade a broad range of bacterial hosts. Nature Microbiology 2024 Jan;9(1):214-227

Galley NF, Greetham D, Alamán-Zárate MG, Williamson MP, Evans CA, Spittal WD, Buddle JE, Freeman J, Davis GL, Dickman MJ, Wilcox MH, Lovering AL, Fagan RP, Mesnage S. Clostridioides difficile canonical L,D-transpeptidases catalyze a novel type of peptidoglycan cross-links and are not required for beta-lactam resistance.J Biol Chem. 2023 Dec 1;300(1):105529

Alamán-Zárate MG, Rady BJ, Evans CA, Pian B, Greetham D, Marecos-Ortiz S, Dickman MJ, Lidbury IDEA, Lovering AL, Barstow BM, Mesnage S. Unusual 1-3 peptidoglycan cross-links in Acetobacteraceae are made by L,D-transpeptidases with a catalytic domain distantly related to YkuD domains. J Biol Chem. 2023 Nov 23;300(1):105494.

Banks EJ, Lambert C, Mason SS, Tyson J, Radford PM, McLaughlin C, Lovering AL, Sockett RE. An MltA-Like Lytic Transglycosylase Secreted by Bdellovibrio bacteriovorus Cleaves the Prey Septum during Predatory Invasion. J Bacteriol. 2023 Apr 25;205(4):e0047522

Al-Jourani, O, Benedict, S, Ross., J, Layton, A, van der Peet, P, Marando, V, Bailey, NP, Heunis, T, Manion, J, Mensitieri, F, Franklin, A, Abellon-Ruiz, J, Oram, SL, Parsons, L, Cartmell, A, Wright, GS, Basle, A, Trost, M, Henrissat, B, Munoz-Munoz, J, Hirt, RP,  Keissling, LL, Lovering, AL, Williams, SJ, Lowe, EC, Moynihan, PJ. (2022). Mining the human gut microbiome identifies mycobacterial D-arabinan degrading enzymes. Nature Communications 2023 Apr 19;14(1):2233

Hespanhol JT, Sanchez-Limache DE, Nicastro GG, Mead L, Llontop EE, Chagas-Santos G, Farah CS, de Souza RF, Galhardo RDS, Lovering AL, Bayer-Santos E. Antibacterial T6SS effectors with a VRR-Nuc domain are structure-specific nucleases. Elife. 2022 Oct 13;11:e82437.

Banks EJ, Valdivia-Delgado M, Biboy J, Wilson A, Cadby IT, Vollmer W, Lambert C, Lovering AL, Sockett RE. Asymmetric peptidoglycan editing generates cell curvature in Bdellovibrio predatory bacteria. Nature Communications 2022; 13, 1509

Meek RW, Cadby IT, Lovering AL. Structures of Bdellovibrio bacteriovorus phosphoglucose isomerase reveal novel rigidity in the active site of a selected subset of enzymes upon substrate binding. Open Biology 2021 Aug;11(8):210098. 

Harding CJ, Cadby IT, Moynihan PJ, Lovering AL. (PhD student Chris Harding as the corresponding author!) A rotary mechanism for allostery in bacterial hybrid malic enzymes. Nature Communications. 2021 Feb 23;12(1):1228. 

Harding CJ, Huwiler SG, Somers H, Lambert C, Ray LJ, Till R, Taylor G, Moynihan PJ, Sockett RE, Lovering AL. A lysozyme with altered substrate specificity facilitates prey cell exit by the periplasmic predator Bdellovibrio bacteriovorus. Nature Communications 11, 4817 (Sept 2020) 

Azmi L, Bragginton EC, Cadby IT, Byron O, Roe AJ, Lovering AL, Gabrielsen M. High-resolution structure of the alcohol dehydrogenase domain of the bifunctional bacterial enzyme AdhE. Acta Crystallogr F Struct Biol Commun. 2020 Sept 1;76(Pt 9):414-421.

Caulton SG, Lovering AL. Bacterial invasion and killing by predatory Bdellovibrio primed by predator prey cell recognition and self protection. Curr Opin Microbiol. 2020 Aug 9;56:74-80

Skotnicka D, Steinchen W, Szadkowski D, Cadby IT, Lovering AL, Bange G, Søgaard-Andersen L. CdbA is a DNA-binding protein and c-di-GMP receptor important for nucleoid organization and segregation in Myxococcus xanthus. Nat Commun. 2020 Apr 14;11(1):1791. doi: 10.1038/s41467-020-15628-8.

Gonzalez LS, Waters-Morgan H, Salamaga B, Robertson AJ, Hounslow AM, Jagielska E, Sabala I, Williamson MP, Lovering AL, Mesnage S. Two site recognition of Staphylococcal peptidoglycan by the lysostaphin SH3b domain. Nature Chemical Biology. 2019 doi: 10.1038/s41589-019-0393-4

Meek RW, Cadby IT, Moynihan PJ, Lovering AL Nature Communications. 2019 Sep 9;10(1):4086. doi: 10.1038/s41467-019-12051-6. PMID:31501441

Lepore R, Kryshtafovych A, Alahuhta M, Veraszto HA, Bomble YJ, Bufton JC, Bullock AN, Caba C, Cao H, Davies OR, Desfosses A, Dunne M, Fidelis K, Goulding CW, Gurusaran M, Gutsche I, Harding CJ, Hartmann MD, Hayes CS, Joachimiak A, Leiman PG, Loppnau P, Lovering AL, Lunin VV, Michalska K, Mir-Sanchis I, Mitra A, Moult J, Phillips GN Jr, Pinkas DM, Rice PA, Tong Y, Topf M, Walton JD, Schwede T.  Proteins. 2019 Aug 23. doi: 10.1002/prot.25805. [Epub ahead of print] PMID:31442339

Cadby IT, Basford SM, Nottingham R, Meek R, Lowry R, Lambert C, Tridgett M, Till R, Ahmad R, Fung R, Hobley L, Hughes WS, Moynihan PJ, Sockett RE, Lovering AL. Mechanism of Nucleotide Signaling Pathway Convergence in a cAMP-sensing c-di-GMP Phosphodiesterase. EMBO J. accepted 2019

Hughes GW, Hall SC, Laxton CS, Sridhar P, Mahadi AH, Hatton C, Piggot TJ, Wotherspoon PJ, Leney AC, Ward DG, Jamshad M, Spana V, Cadby IT, Harding C, Isom GL, Bryant JA, Parr RJ, Yakub Y, Jeeves M, Huber D, Henderson IR, Clifton LA, Lovering AL, Knowles TJ. Evidence for phospholipid export from the bacterial inner membrane by the Mla ABC transport system. Nature Microbiol. 2019 doi: 10.1038/s41564-019-0481-y

Moynihan PJ, Maceiras AR, Cadby IT, Veerapen N, Jankute M, Crosatti M, Mukamolova GV, Saraiva M, Lovering AL, Besra GS. The hydrolase LpqI primes mycobacterial peptidoglycan recycling. Nature Communications. 2019;10(1):2647          

Ba X, Coll F, Blane B, Restif O, Carvell H, Köser C, Jamrozy D, Reuter S, Lovering AL, Gleadall N, Bellis K, Uhlemann A, Lowy F, Massey R, Grilo I, Sobral R, Larsen J, Larsen A, Vingsbo Lundberg C, Parkhill J, Paterson G, Holden M, Peacock S, Holmes M, Harrison E. Genomic identification of cryptic susceptibility to penicillins and β-lactamase inhibitors in methicillin-resistant Staphylococcus aureus. Nature Microbiol. 2019 doi: 10.1038/s41564-019-0471-0

Cadby IT, Ibrahim SA, Faulkner M, Lee DJ, Browning D, Busby SJ, Lovering AL, Stapleton MR, Green J, Cole JA. Regulation, sensory domains and roles of two Desulfovibrio desulfuricans ATCC27774 Crp family transcription factors, HcpR1 and HcpR2, in response to nitrosative stress. Mol Microbiol. 2016 102(6):1120-1137

Lambert C, Lerner TR, Bui NK, Somers H, Aizawa S, Liddell S, Clark A, Vollmer W, Lovering AL, Sockett RE.  Sci Rep. 2016 May 23;6:26010.

Rajasekar KV, Lovering AL, Dancea F, Scott DJ, Harris SA, Bingle LE, Roessle M, Thomas CM, Hyde EI, White SA.  Nucleic Acids Res. 2016 Mar 25.

Lambert C, Cadby IT, Till R, Bui NK, Lerner TR, Hughes WS, Lee DJ, Alderwick LJ, Vollmer W, Sockett ER, Lovering AL. Ankyrin-mediated self-protection during cell invasion by the bacterial predator Bdellovibrio bacteriovorus. Nature Communications. 2015 Dec 2;6:8884.

Ba X, Harrison EM, Lovering AL, Gleadall N, Zadoks R, Parkhill J, Peacock SJ, Holden MT, Paterson GK, Holmes MA. Old drugs to treat resistant bugs: methicillin-resistant Staphylococcus aureus isolates with mecC are susceptible to a combination of penicillin and clavulanic acid.
Antimicrob Agents Chemother. 2015 pii: AAC.01469-15

Prehna G, Ramirez, BE, Lovering AL. The Lifestyle Switch Protein Bd0108 of Bdellovibrio bacteriovorus is an Intrinsically Disordered Protein. PLoS One Dec 2014; 9(12):e115390
[recommended by Faculty of 1000]

Cadby IT, Lovering AL. Molecular Surveillance of the Subtle Septum: Discovering a New Mode of Peptidoglycan Synthesis in Streptococci. Mol Micro. 2014;

Cadby IT, Lovering AL. Life in the “Old Bag” Yet: Structure of Peptidoglycan L,D-Carboxypeptidases. Structure. 2014; 22(7): 932-4.

David S. Milner, Rob Till, Ian Cadby, Andrew L. Lovering, Sarah M. Basford, Emma B. Saxon, Susan Liddell, Laura E. Williams, R. Elizabeth Sockett Research Article | published 10 Apr 2014 | PLOS Genetics 10.1371/journal.pgen.1004253

Robert J. Gruninger, John Thibault, Michael J. Capeness, Robert Till, Steven C. Mosimann, R. Elizabeth Sockett, Brent L. Selinger, Andrew L. Lovering
Research Article | published 09 Apr 2014 | PLOS ONE 10.1371/journal.pone.0094403

Capeness MJ, Lambert C, Lovering AL, Uchida K, Chaudhuri R, Alderwick  LJ, Lee DJ­,Swarbreck D, Till R, Aizawa S-I , Sockett RE. Activity of Bdellovibriohit Locus Proteins, Bd0108 and Bd0109, Links Type IVa Pilus Extrusion/Retraction Status to Prey-Independent Growth Signalling. PLOS ONE Nov 2013; 10.1371/journal.pone.0079759

Lovering AL, Gretes MC, Safadi SS, Danel F, De Castro L, Page MG, Strynadka NC. Structural Insights into the Anti- Methicillin-Resistant Staphylococcus aureus (MRSA) Activity of Ceftobiprole. J Biol Chem. 2012 (Epub)

Anwari K, Webb CT, Poggio S, Perry AJ, Belousoff M, Celik N, Ramm G, Lovering A, Sockett RE, Smit J, Jacobs-Wagner C, Lithgow T.  The Evolution of New Protein Subunits of the Bacterial Outer Membrane BAM Complex. Mol Microbiol. 2012 84(5) 832-44

, , , . Structure and function of Mycobacterium tuberculosis meso-di aminopimelic acid (DAP) biosynthetic enzymes. 2012 Feb 16. doi: 10.1111
PubMed link: 

, , , , , , . Specialized Peptidoglycan Hydrolases Sculpt the Intra-bacterial Niche of Predatory Bdellovibrio and Increase Population Fitness. 2012 Feb;8(2):e1002524.
PubMed link: 

The Structure of an unconventional HD-GYP Protein from BdellovibrioReveals the Roles of Conserved Residues in This Class of Cyclic-di-GMP Phosphodiesterases. mBio. 2011 Oct 11;2(5).

Lovering AL, Safadi SS, Strynadka NCJ. Structural Perspective of Peptidoglycan Biosynthesis and Assembly. Ann Rev Biochem.2012 81. Accepted Sept 2011.

Identification of novel diphenyl urea inhibitors of Mt-GuaB2 active against Mycobacterium tuberculosis. Microbiology. 2011 157(1) 290-9.

Biochemical characterization of the Mycobacterium tuberculosisphosphoribosyl-1-pyrophosphate synthetase. Glycobiology. 2011 21(4) 410-25.

Dimerization and DNA-dependent aggregation of the Escherichia colinucleoid protein and chaperone CbpA. Mol Microbiol. 2010 77(5) 1289-300.

Structure of the cell wall teichoic acid polymerase TagF: details of membrane-binding and catalysis. Nature Struct Mol Biol. 2010 17(5) 582-9.

Identification of dynamic structural motifs involved in peptidoglycan glycosyltransfer. J Mol Biol. 2008 Oct 31;383(1):167-77.

Structural details of the glycosyltransferase step of peptidoglycan assembly. Curr Opin Struct Biol. 2008 : 18(5) 534-43.

High-resolution structure of the major periplasmic domain from the cell shape-determining filament MreC. J Mol Biol. 2007 Sep 28;372(4):1034-44.

The crystal structure of the cytosolic exopolyphosphatase from Saccharomyces cerevisiae reveals the basis for substrate specificity. J Mol Biol. 2007 Aug 24;371(4):1007-21.

Kinetic and structural characterisation of Escherichia coli nitroreductase mutants showing improved efficacy for the prodrug substrate CB1954. J Mol Biol. 2007 Apr 27;368(2):481-92.

Structural insight into the transglycosylation step of bacterial cell-wall biosynthesis. Science. 2007 Mar 9;315(5817):1402-5.

Structural analysis of an "open" form of PBP1B from Streptococcus pneumoniae. Protein Sci. 2006 Jul;15(7):1701-9.

Expanding the thioglycoligase strategy to the synthesis of alpha-linked thioglycosides allows structural investigation of the parent enzyme/substrate complex. J Am Chem Soc. 2006 Feb 22;128(7):2202-3.

Beta-lactam antibiotic resistance: a current structural perspective. Curr Opin Microbiol. 2005 Oct;8(5):525-33. (*equal authorship)

Phasing in the presence of radiation damage. J Synchrotron Radiat.2005 May;12(Pt 3):276-84.

Structural and mechanistic studies of Escherichia coli nitroreductase with the antibiotic nitrofurazone. Reversed binding orientations in different redox states of the enzyme. J Biol Chem. 2005 Apr 8;280(14):13256-64.

  Structural and mechanistic analysis of sialic acid synthase NeuB from Neisseria meningitidis in complex with Mn2+, phosphoenolpyruvate, and N-acetylmannosaminitol. J Biol Chem. 2005 Feb 4;280(5):3555-63.

Mechanistic and structural analysis of a family 31 alpha-glycosidase and its glycosyl-enzyme intermediate. J Biol Chem. 2005 Jan 21;280(3):2105-15.

Nitroreductase: a prodrug-activating enzyme for cancer gene therapy. Clin Exp Pharmacol Physiol. 2004 Nov;31(11):811-6

  Structural and biochemical identification of a novel bacterial oxidoreductase. J Biol Chem.2004 Nov 26;279(48):50391-400.

Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin. Cancer Res. 2004 Mar 1;64(5):1802-10.

Generation of Escherichia coli nitroreductase mutants conferring improved cell sensitization to the prodrug CB1954. Cancer Res.2003 Sep 1;63(17):5532-7.

The structure of Escherichia coli nitroreductase complexed withnicotinic acid: three crystal forms at 1.7 A, 1.8 A and 2.4 A resolution. J Mol Biol. 2001 May 25;309(1):203-13.