Antibiotic discovery in the twenty-first century: current trends and future perspectives

New antibiotics are necessary to treat microbial pathogens that are becoming increasingly resistant to available treatment. Despite the medical need, the number of newly approved drugs continues to decline. We offer an overview of the pipeline for new antibiotics at different stages, from compounds in clinical development to newly discovered chemical classes. Consistent with historical data, the majority of antibiotics under clinical development are natural products or derivatives thereof. However, many of them also represent improved variants of marketed compounds, with the consequent risk of being only partially effective against the prevailing resistance mechanisms. In the discovery arena, instead, compounds with promising activities have been obtained from microbial sources and from chemical modification of antibiotic classes other than those in clinical use. Furthermore, new natural product scaffolds have also been discovered by ingenious screening programs. After providing selected examples, we offer our view on the future of antibiotic discovery.

[1]  Andrew G Myers,et al.  A Convergent Enantioselective Route to Structurally Diverse 6-Deoxytetracycline Antibiotics , 2005, Science.

[2]  T. File.  A Phase 2 Study Comparing Two Doses of Radezolid to Linezolid in Adults with Uncomplicated Skin and Skin Structure Infections (uSSSI) , 2008 .

[3]  Harald Gross,et al.  The genomisotopic approach: a systematic method to isolate products of orphan biosynthetic gene clusters. , 2007, Chemistry & biology.

[4]  S. Donadio,et al.  Strategies for the isolation and characterization of antibacterial lantibiotics. , 2010, Methods in molecular biology.

[5]  H. Reichenbach,et al.  Thuggacins, macrolide antibiotics active against Mycobacterium tuberculosis: isolation from myxobacteria, structure elucidation, conformation analysis and biosynthesis. , 2007, Chemistry.

[6]  K. Bush,et al.  A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin-structure infections. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[7]  D. Boger,et al.  Functional and biochemical analysis of a key series of ramoplanin analogues. , 2009, Bioorganic & medicinal chemistry letters.

[8]  Emmanuel Zazopoulos,et al.  Microbial genomics as a guide to drug discovery and structural elucidation: ECO-02301, a novel antifungal agent, as an example. , 2005, Journal of natural products.

[9]  R. P. Ross,et al.  Identification of a novel two-peptide lantibiotic, haloduracin, produced by the alkaliphile Bacillus halodurans C-125. , 2007, FEMS microbiology letters.

[10]  F. Castiglione,et al.  Determining the structure and mode of action of microbisporicin, a potent lantibiotic active against multiresistant pathogens. , 2008, Chemistry & biology.

[11]  C. Farnet,et al.  Genomic analyses lead to novel secondary metabolites. Part 3. ECO-0501, a novel antibacterial of a new class. , 2006, The Journal of antibiotics.

[12]  H. Kolb,et al.  The growing impact of click chemistry on drug discovery. , 2003, Drug discovery today.

[13]  J. Phillips,et al.  Highly sensitive target-based whole-cell antibacterial discovery strategy by antisense RNA silencing. , 2007, Current opinion in drug discovery & development.

[14]  H. Sahl,et al.  Production of the Novel Two-Peptide Lantibiotic Lichenicidin by Bacillus licheniformis DSM 13 , 2009, PloS one.

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

[16]  Dongwoo Shin,et al.  Alanine scan of [L-Dap(2)]ramoplanin A2 aglycon: assessment of the importance of each residue. , 2007, Journal of the American Chemical Society.

[17]  U. Theuretzbacher,et al.  Future antibiotics scenarios: is the tide starting to turn? , 2009, International journal of antimicrobial agents.

[18]  S. Donadio,et al.  Chapter 1. Approaches to discovering novel antibacterial and antifungal agents. , 2009, Methods in enzymology.

[19]  D. Livermore,et al.  Activity of the siderophore monobactam BAL30072 against multiresistant non-fermenters. , 2010, The Journal of antimicrobial chemotherapy.

[20]  F. Vasile,et al.  Structure revision of the lantibiotic 97518. , 2009, Journal of natural products.

[21]  David J Newman,et al.  Natural products as leads to potential drugs: an old process or the new hope for drug discovery? , 2008, Journal of medicinal chemistry.

[22]  I. D. Jenkins,et al.  Multisite modification of neomycin B: combined Mitsunobu and click chemistry approach. , 2007, The Journal of organic chemistry.

[23]  A. Bull,et al.  Abyssomicin C:A Polycyclic Antibiotic from a Marine Verrucosispora Strain as an Inhibitor of the p‐Aminobenzoic Acid/Tetrahydrofolate Biosynthesis Pathway. , 2004 .

[24]  H. Naegeli,et al.  Ribosomally synthesized thiopeptide antibiotics targeting elongation factor Tu. , 2009, Journal of the American Chemical Society.

[25]  C. Walsh,et al.  Generation of thiocillin variants by prepeptide gene replacement and in vivo processing by Bacillus cereus. , 2009, Journal of the American Chemical Society.

[26]  C. Farnet,et al.  Genomic Analyses Lead to Novel Secondary Metabolites , 2006, The Journal of Antibiotics.

[27]  M. Maccoss,et al.  Synthesis and biological evaluation of platensimycin analogs. , 2009, Bioorganic & medicinal chemistry letters.

[28]  A. Stepan,et al.  Design, synthesis, and biological evaluation of platensimycin analogues with varying degrees of molecular complexity. , 2008, Journal of the American Chemical Society.

[29]  A. Demain.  Prescription for an ailing pharmaceutical industry , 2002, Nature Biotechnology.

[30]  L. Naesens,et al.  Diazo transfer-click reaction route to new, lipophilic teicoplanin and ristocetin aglycon derivatives with high antibacterial and anti-influenza virus activity: an aggregation and receptor binding study. , 2009, Journal of medicinal chemistry.

[31]  N. Kaplan,et al.  In Vitro Activity of API-1252, a Novel FabI Inhibitor, against Clinical Isolates of Staphylococcus aureus and Staphylococcus epidermidis , 2007, Antimicrobial Agents and Chemotherapy.

[32]  J. Willey,et al.  Lantibiotics: peptides of diverse structure and function. , 2007, Annual review of microbiology.

[33]  F. Castiglione,et al.  Synthesis and preliminary biological characterization of new semisynthetic derivatives of ramoplanin. , 2007, Journal of medicinal chemistry.

[34]  M. Kurz,et al.  Antibiotics GE23077, novel inhibitors of bacterial RNA polymerase. I. Taxonomy, isolation and characterization. , 2004, The Journal of antibiotics.

[35]  Hai-yin He.  Mannopeptimycins, a novel class of glycopeptide antibiotics active against gram-positive bacteria , 2005, Applied Microbiology and Biotechnology.

[36]  C. Lerner,et al.  A robust platform for the synthesis of new tetracycline antibiotics. , 2008, Journal of the American Chemical Society.

[37]  M. Cavaleri,et al.  Human pharmacokinetics and rationale for once-weekly dosing of dalbavancin, a semi-synthetic glycopeptide. , 2005, The Journal of antimicrobial chemotherapy.

[38]  Scott K. Smith,et al.  Isolation, structure, and antibacterial activity of philipimycin, a thiazolyl peptide discovered from Actinoplanes philippinensis MA7347. , 2008, Journal of the American Chemical Society.

[39]  B. Rudd,et al.  Organization of the genes encoding the biosynthesis of actagardine and engineering of a variant generation system , 2009, Molecular microbiology.

[40]  C. Gualerzi,et al.  Novel tetrapeptide inhibitors of bacterial protein synthesis produced by a Streptomyces sp. , 2006, Biochemistry.

[41]  R. Süssmuth,et al.  Abyssomicins G and H and atrop-Abyssomicin C from the Marine Verrucosispora Strain AB-18-032† , 2007, The Journal of Antibiotics.

[42]  R. Bonomo,et al.  ACHN-490, a Neoglycoside with Potent In Vitro Activity against Multidrug-Resistant Klebsiella pneumoniae Isolates , 2009, Antimicrobial Agents and Chemotherapy.

[43]  M. Souli,et al.  Emergence of extensively drug-resistant and pandrug-resistant Gram-negative bacilli in Europe. , 2008, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[44]  R. Bonomo,et al.  In Vitro Activity of NXL104 in Combination with β-Lactams against Klebsiella pneumoniae Isolates Producing KPC Carbapenemases , 2009, Antimicrobial Agents and Chemotherapy.

[45]  Jun Wang,et al.  Platensimycin is a selective FabF inhibitor with potent antibiotic properties , 2006, Nature.

[46]  A. Girard,et al.  In vitro activity of the β-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases , 2009, The Journal of antimicrobial chemotherapy.

[47]  H. Sahl,et al.  The Lipopeptide Antibiotic Friulimicin B Inhibits Cell Wall Biosynthesis through Complex Formation with Bactoprenol Phosphate , 2009, Antimicrobial Agents and Chemotherapy.

[48]  Mark S Butler,et al.  Natural products to drugs: natural product derived compounds in clinical trials. , 2005, Natural product reports.

[49]  W. A. van der Donk,et al.  Insights into the Mode of Action of the Two-Peptide Lantibiotic Haloduracin , 2009, ACS chemical biology.

[50]  A. Stepan,et al.  Total synthesis and antibacterial properties of carbaplatensimycin. , 2007, Journal of the American Chemical Society.

[51]  P. Bradford,et al.  Late stage antibacterial drugs in the clinical pipeline. , 2007, Current opinion in microbiology.

[52]  B. Murray,et al.  Antibiotic-resistant bugs in the 21st century--a clinical super-challenge. , 2009, New England Journal of Medicine.

[53]  M. Motyl,et al.  Antibacterial evaluations of thiazomycin- a potent thiazolyl peptide antibiotic from Amycolatopsis fastidiosa. , 2008, Journal of antibiotics (Tokyo. 1968).

[54]  C. Gualerzi,et al.  Specific, efficient, and selective inhibition of prokaryotic translation initiation by a novel peptide antibiotic. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[55]  N. Woodford,et al.  NXL104 combinations versus Enterobacteriaceae with CTX-M extended-spectrum beta-lactamases and carbapenemases. , 2008, The Journal of antimicrobial chemotherapy.

[56]  Arnold L. Demain,et al.  Contributions of Microorganisms to Industrial Biology , 2008, Molecular biotechnology.

[57]  F. Ikeda,et al.  In Vitro and In Vivo Activities of a New Cephalosporin, FR264205, against Pseudomonas aeruginosa , 2006, Antimicrobial Agents and Chemotherapy.

[58]  M. Wilcox,et al.  Effects of Exposure of Clostridium difficile PCR Ribotypes 027 and 001 to Fluoroquinolones in a Human Gut Model , 2008, Antimicrobial Agents and Chemotherapy.

[59]  M. Motyl,et al.  Antibacterial Evaluations of Thiazomycin , 2007, The Journal of Antibiotics.

[60]  F. Koehn.  New strategies and methods in the discovery of natural product anti-infective agents: the mannopeptimycins. , 2008, Journal of medicinal chemistry.