Polishing the tarnished silver bullet: the quest for new antibiotics

We are facing a potential catastrophe of untreatable bacterial infections, driven by the inexorable rise of extensively drug-resistant bacteria, coupled with a market failure of pharmaceutical and biotech companies to deliver new therapeutic options. While global recognition of the problem is finally apparent, solutions are still a long way from being implemented. In addition to drug stewardship programmes and better diagnostics, new antibiotics are desperately needed. The question remains as to how to achieve this goal. This review will examine the different strategies being applied to discover new antibiotics.

[1]  S. Shapiro.  Speculative strategies for new antibacterials: all roads should not lead to Rome , 2013, The Journal of Antibiotics.

[2]  Spencer J. Williams,et al.  Corrigendum: Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism , 2015, Nature.

[3]  S. Reardon.  Antibiotic resistance sweeping developing world , 2014, Nature.

[4]  F. Romesberg,et al.  Structural and initial biological analysis of synthetic arylomycin A2. , 2007, Journal of the American Chemical Society.

[5]  G. Franck.  Open access , 2012, Cell cycle.

[6]  Nick Bassiliades,et al.  Preface , 2018, Int. J. Artif. Intell. Tools.

[7]  Alan P. Johnson.  Surveillance of antibiotic resistance , 2015, Philosophical Transactions of the Royal Society B: Biological Sciences.

[8]  C. Walsh,et al.  Prospects for new antibiotics: a molecule-centered perspective , 2013, The Journal of Antibiotics.

[9]  S. Stevanović,et al.  Arylomycins A and B, new biaryl-bridged lipopeptide antibiotics produced by Streptomyces sp. Tü 6075. II. Structure elucidation. , 2002, The Journal of antibiotics.

[10]  P. Fernandes,et al.  The global challenge of new classes of antibacterial agents: an industry perspective. , 2015, Current opinion in pharmacology.

[11]  B. Brooks,et al.  Therapeutic strategies to combat antibiotic resistance. , 2014, Advanced drug delivery reviews.

[12]  David Tweats,et al.  Fexinidazole – A New Oral Nitroimidazole Drug Candidate Entering Clinical Development for the Treatment of Sleeping Sickness , 2010, PLoS neglected tropical diseases.

[13]  M. Cooper.  A community-based approach to new antibiotic discovery , 2015, Nature Reviews Drug Discovery.

[14]  R. Anderson.  Antimicrobial resistance: addressing the threat to global health. Preface. , 2015, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[15]  A. Patchett,et al.  Antibacterial Agents That Inhibit Lipid A Biosynthesis , 1996, Science.

[16]  Michael A. Skinnider,et al.  Genomic charting of ribosomally synthesized natural product chemical space facilitates targeted mining , 2016, Proceedings of the National Academy of Sciences.

[17]  D. Pompliano,et al.  Drugs for bad bugs: confronting the challenges of antibacterial discovery , 2007, Nature Reviews Drug Discovery.

[18]  C. L. Ventola,et al.  The antibiotic resistance crisis: part 2: management strategies and new agents. , 2015, P & T : a peer-reviewed journal for formulary management.

[19]  Corie Lok,et al.  Mining the microbial dark matter , 2015, Nature.

[20]  R. García-Contreras,et al.  Drug repurposing as an alternative for the treatment of recalcitrant bacterial infections , 2015, Front. Microbiol..

[21]  Shailesh V. Date,et al.  A Putative Bacterial ABC Transporter Circumvents the Essentiality of Signal Peptidase , 2016, mBio.

[22]  Tom A Fowler,et al.  Tackling the threat of antimicrobial resistance: from policy to sustainable action , 2015, Philosophical Transactions of the Royal Society B: Biological Sciences.

[23]  F. Romesberg,et al.  Mechanism of Action of the Arylomycin Antibiotics and Effects of Signal Peptidase I Inhibition , 2012, Antimicrobial Agents and Chemotherapy.

[24]  R. Draheim,et al.  Written evidence to the Select Committee on Science and Technology concerning Antimicrobial resistance (AMR) and the UK Five Year Antimicrobial Resistance Strategy. , 2013 .

[25]  Sheo B. Singh.  Confronting the challenges of discovery of novel antibacterial agents. , 2014, Bioorganic & medicinal chemistry letters.

[26]  Ying Huang,et al.  Activation and Identification of NC-1: A Cryptic Cyclodepsipeptide from Red Soil-Derived Streptomyces sp. FXJ1.172 , 2016 .

[27]  M. Ward,et al.  Sources of Antimicrobial Resistance , 2013, Science.

[28]  F. Romesberg,et al.  The inhibition of type I bacterial signal peptidase: Biological consequences and therapeutic potential. , 2015, Bioorganic & medicinal chemistry letters.

[29]  Waleed Younis,et al.  Repurposing Non-Antimicrobial Drugs and Clinical Molecules to Treat Bacterial Infections. , 2015, Current pharmaceutical design.

[30]  E. Meyers,et al.  A nomenclature proposal for the octapeptin antibiotics. , 1976, The Journal of antibiotics.

[31]  K. Lewis,et al.  Erratum: A new antibiotic kills pathogens without detectable resistance , 2015, Nature.

[32]  Kieron M. G. O'Connell,et al.  Combating multidrug-resistant bacteria: current strategies for the discovery of novel antibacterials. , 2013, Angewandte Chemie.

[33]  F. Romesberg,et al.  Initial efforts toward the optimization of arylomycins for antibiotic activity. , 2011, Journal of medicinal chemistry.

[34]  David Brown,et al.  Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void? , 2015, Nature Reviews Drug Discovery.

[35]  R. Meek,et al.  Nonmedical Uses of Antibiotics: Time to Restrict Their Use? , 2015, PLoS biology.

[36]  F. Romesberg,et al.  Synthesis and biological characterization of arylomycin B antibiotics. , 2011, Journal of natural products.

[37]  K. Lewis,et al.  A new antibiotic kills pathogens without detectable resistance , 2015, Nature.

[38]  R. Pukall,et al.  Arylomycins A and B, new biaryl-bridged lipopeptide antibiotics produced by Streptomyces sp. Tü 6075. I. Taxonomy, fermentation, isolation and biological activities. , 2002, The Journal of antibiotics.

[39]  F. Aarestrup.  The livestock reservoir for antimicrobial resistance: a personal view on changing patterns of risks, effects of interventions and the way forward , 2015, Philosophical Transactions of the Royal Society B: Biological Sciences.

[40]  M. Page,et al.  Crystallographic and Biophysical Analysis of a Bacterial Signal Peptidase in Complex with a Lipopeptide-based Inhibitor* , 2004, Journal of Biological Chemistry.

[41]  Matthew A Cooper,et al.  Chemical philanthropy: a path forward for antibiotic discovery? , 2016, Future medicinal chemistry.

[42]  G. B. Golding,et al.  Antibiotic resistance is ancient , 2011, Nature.

[43]  M. Cooper,et al.  Helping Chemists Discover New Antibiotics. , 2015, ACS infectious diseases.

[44]  F. Romesberg,et al.  Efforts toward broadening the spectrum of arylomycin antibiotic activity. , 2013, Bioorganic & medicinal chemistry letters.

[45]  E. Leach.  Resistance fighters. , 1999, Nursing times.

[46]  Dean G. Brown,et al.  ESKAPEing the labyrinth of antibacterial discovery , 2015, Nature Reviews Drug Discovery.

[47]  C. L. Ventola.  The antibiotic resistance crisis: part 1: causes and threats. , 2015, P & T : a peer-reviewed journal for formulary management.

[48]  Dale Dominey-Howes,et al.  Why emergency management should be interested in the emergence of antibiotic resistance , 2014 .

[49]  J. Farrar,et al.  Antimicrobial resistance in humans, livestock and the wider environment , 2015, Philosophical Transactions of the Royal Society B: Biological Sciences.

[50]  G. Rossolini,et al.  Update on the antibiotic resistance crisis. , 2014, Current opinion in pharmacology.

[51]  D. Dominey-Howes,et al.  The Antimicrobial Resistance Crisis: Causes, Consequences, and Management , 2014, Front. Public Health.

[52]  Ryan A McClure,et al.  In Vitro Reconstruction of Nonribosomal Peptide Biosynthesis Directly from DNA Using Cell-Free Protein Synthesis. , 2017, ACS synthetic biology.

[53]  D. Kalinin,et al.  Insights into the Zinc-Dependent Deacetylase LpxC: Biochemical Properties and Inhibitor Design. , 2016, Current topics in medicinal chemistry.

[54]  P. Kulanthaivel,et al.  Novel Lipoglycopeptides as Inhibitors of Bacterial Signal Peptidase I* , 2004, Journal of Biological Chemistry.

[55]  K. Servick.  The drug push. , 2015, Science.

[56]  E. Bettiol,et al.  Development of new antibiotics: taking off finally? , 2015, Swiss medical weekly.

[57]  Editorial overview: Anti-infectives: Current challenges and unmet needs in antimicrobial therapy. , 2015, Current opinion in pharmacology.