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Antibiotics in the Clinical Pipeline in 2011

Antibiotics in the Clinical Pipeline in 2011

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REVIEW ARTICLE
Antibiotics in the clinical pipeline in 2011
Mark S Butler and Matthew A Cooper
The emergence of multi-drug-resistant bacteria and the lack of new antibiotics in the antibiotic drug development pipeline,especially those with new modes of action, is a major health concern. This review lists the 20 new antibiotics launchedsince 2000 and records the 40 compounds currently in active clinical development. Compounds in the pipeline from newantibiotic classes are reviewed in detail with reference to their development status, mode of action, spectrum of activityand lead discovery. In addition, the NP or synthetic derivation is discussed, with activity against Gram-negative bacteriahighlighted.
The Journal of Antibiotics 
(2011)
64,
413–425; doi:10.1038/ja.2011.44; published online 18 May 2011
Keywords:
clinical trials; drug development; drug discovery; natural product; resistance
INTRODUCTION
The discovery of sulfonamides and
b
-lactam antibiotics in the 1930shad a profound impact on human health by enabling rapid treatmentof patients with bacterial infections that previously had often provedfatal.
Over the next 40 years, now seen as the ‘‘golden era’’ of antibiotic research, the majority of antibiotic drug classes in use today were discovered. Since 1970, most newly approved antibiotics (seeTable 1for antibiotics launched since 2000) have been based on theseknown scaffolds, with the exception of linezolid (
1
), an oxazolidinone;daptomycin (
2
), a lipopeptide; and the topical antibiotics mupirocin(launched 1985), a pseudomonic acid, and retapamulin (
3
), a pleur-omutilin derivative.
3
The lack of new antibiotics, the emergence of multi-drug-resistantbacteria and the economic and regulatory challenges of antibioticresearch have been discussed in depth.
The potential for a majorantibiotic healthcare crisis is best summarized by the InfectiousDiseases Society of America (IDSA)
and the European Centrefor Disease Prevention and Control,
both of which report thatthere are only a few potential drugs in clinical development that (1)offer significant benefits over existing drugs and (2) that target Gram-negative, hospital-based infections. Gram-negative bacteria are espe-cially difficult to kill as they have an additional outer membranepermeability barrier that compounds need to surmount to be effica-cious, as well as often possessing multiple efflux pumps, and antibioticand target-modifying enzymes.
Despite these considerable chal-lenges, antibiotic drug development is in fact well validated, with ahistorically high approval rate following successful completion of phase-I studies.
This article reviews all antibiotics that have been launched since2000, and compounds that are currently undergoing clinical develop-ment in phase-I, II or III trials, and under regulatory evaluation as of early 2011. Compounds representing new antibiotic classes arereviewed in detail with reference to their development status, modeof action, spectra of activity and historical discovery. New combina-tions of previously approved antibiotics have not been included. Inaddition, the origin of the drug pharmacophore; the natural product(NP) or synthetic derivation, is also reviewed. These data wereobtained by reviewing the journal literature and internet resourcessuch as company webpages, clinical trial registers and biotechnology-related newsletters. Some compounds where there has been noevidence of recent development have been excluded from this review.Every endeavor has been undertaken to ensure that these data areaccurate, but it is possible that compounds undergoing early clinicaldevelopment have been overlooked.The drug development and approval process, as well as commonly used abbreviations associated with antibiotic development used in thisreview, are summarized as follows:
Before clinical trials can start, an Investigational New DrugApplication (IND) must be approved by the US Food andDrug Administration (FDA), European Medicines Agency (EMA),Japanese Pharmaceuticals and Medical Devices Agency (PMDA)or equivalent agency.
The clinical indication for clinical trial approval in general fallswithin one of the following categories of antibacterial infections:
Clostridium difficile
infections (CDI),
C. difficile
-associated diarrhea(CDAD), skin and skin structure infections (SSSi), which are furtherdivided into complicated (cSSSi), uncomplicated (uSSSi) and acutebacterial (ABSSSi), community/hospital acquired pneumonia (CAP/HAP), community-acquired bacterial pneumonia (CABP), urinary tract infections (UTI), complicated intra-abdominal infections(cIAI) and tuberculosis (TB).
Received 10 March 2011; revised 10 April 2011; accepted 20 April 2011; published online 18 May 2011Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, AustraliaCorrespondence: Professor MA Cooper, Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Queensland BiosciencesPrecinct, 306 Carmody Road, St Lucia, Brisbane, Queensland 4072, Australia.E-mail:m.cooper@uq.edu.au
The Journal of Antibiotics (2011) 64,
413–425
&
2011 Japan Antibiotics Research Association All rights reserved 0021-8820/11 $32.00
 
Upon successful completion of phase-III clinical trials, a New DrugApplication (NDA/FDA and PMDA) or a Marketing AuthorizationApplication (MAA/EMA) must be submitted to seek approval tobe able to market the drug.
ANTIBACTERIAL DRUGS LAUNCHED SINCE 2000
Since 2000, 20 new antibiotics have been launched worldwide (Table 1;Figures 1 and 2), of which 11 are NP-derived and nine are synthe-tically derived. A majority of the NP-derived antibiotics belong tothe
b
-lactam class, with the other five belonging to separate classes.Noteworthy among the NP-derived antibiotics are daptomycin (
2
)and retapamulin (
3
), the first members of the lipopeptide andpleuromutilin classes, respectively, approved for use in humans.Within the synthetically derived antibiotics there is minimal diversity,with eight of the nine antibiotics belonging to the quinolone class andlinezolid (
1
), which is the first and, to date, the only representative of the oxazolidinone class.
COMPOUNDS UNDERGOING CLINICAL EVALUATION
This section describes compounds and their structures currently undergoing clinical trials and under regulatory evaluation for thetreatment of bacterial infections as of early 2011 (phase-III/(NDA) inTable 2, with structures inFigure 3; phase-II inTable 3, with structures inFigures 3 and 4; and phase-I inTable 4, with structures inFigure 7). Compounds that represent new antibiotic classes are underlined in thetables and a summary of their development status, mode of action anddiscovery is discussed in detail.
Phase-III trials and NDA/MAA applications
Fidaxomicin (
21
), which is being developed by Optimer Pharmaceu-ticals (San Diego, CA, USA), is currently undergoing evaluation formarket approval by the FDA (NDA finalized in November 2010) andEMA (MAA submitted in September 2010) for the treatment of patients with CDIs.
C. difficile
is a spore-forming Gram-positiveanaerobe that can cause serious intestinal infections through secretedtoxins that cause inflammation of the colon, severe diarrhea, feverwith an elevated white blood cell count, and intestinal paralysis andsepsis in widespread infections.
CDI can be lethal, especially incompromised patients, and there are increasing worldwide outbreaksof new virulent and highly toxic strains of 
C. difficile
.
Currently only metronidazole and vancomycin are routinely used to treat CDI, anddevelopment of new agents is urgently required.
Data from twophase-III trials indicated that fidaxomicin (
21
) was able to achieve theprimary endpoint of clinical cure, which was defined as patients notrequiring any further CDI therapy 2 days after the completion of thefidaxomicin (
21
) course.
In addition, fidaxomicin (
21
) showed ahigher global cure rate than vancomycin and a lower recurrence rate,which was defined as no recurrence within 4 weeks. Fidaxomicin (
21
)belongs to a family of actinomycete-derived macrolactone with acomplex history. The structure of 
21
, which was named tiacumicin-B,and a series of analogs were reported by Abbott Laboratories in apatent filed in 1986
and published in 1987.
Fidaxomicin (
21
)and analogs have identical structures to the lipiarmycins whoseisolation and biological activity, and structure elucidation, werereported in 1975
and 1987
respectively, and the clostomicinswhose activity and structures were reported in 1986.
Early on thesemacrolactones were shown to be inhibitors of the bacterial DNA-dependent RNA polymerase.
Recent studies have shown thatthese macrolactones impede the
de novo
initiation of RNA synthesisthrough binding to the o´70-subunit region-3.2 and the RNA poly-merase
b
¢
-subunit switch-2 element, which controls the clamping of the promoter DNA in the RNA polymerase active-site cleft.
In
Table 1 New antibacterial drugs launched since 2000 divided into NP- and synthetically-derived listed by antibiotic class
Year Name Class Lead (sourceNP-derived 
2002 Biapenem (
4
)
b
-Lactam (carbapenem) Thienamycin (actinomycete)2002 Ertapenem (
5
)
b
-Lactam (carbapenem) Thienamycin (actinomycete)2005 Doripenem (
6
)
b
-Lactam (carbapenem) Thienamycin (actinomycete)2009 Tebipenem pivoxil (
7
)
b
-Lactam (carbapenem) Thienamycin (actinomycete)2008 Ceftobiprole medocaril (
8
)
b
-Lactam (cephalosporin) Cephalosporin (fungus)2010 Ceftaroline fosamil (
9
)
b
-Lactam (cephalosporin) Cephalosporin (fungus)2001 Telithromycin (
10
) Macrolide (ketolide) Erythromycin (actinomycete)2003 Daptomycin (
2
)
a
Lipopeptide Daptomycin (actinomycete)2005 Tigecycline (
11
) Tetracycline Tetracycline (actinomycete)2007 Retapamulin (
3
)
a,b
Pleuromutilin Pleuromutilin (fungus)2009 Telavancin (
12
) Glycopeptide Vancomycin (actinomycete)
Synthetically-derived 
2000 Linezolid (
1
)
a
Oxazolidinone Oxazolidinone2002 Prulioxacin (
13
) Fluoroquinolone Quinolone2002 Pazuoxacin (
14
) Fluoroquinolone Quinolone2002 Balooxacin (
15
) Fluoroquinolone Quinolone2004 Gemioxacin (
16
) Fluoroquinolone Quinolone2007 Garenoxacin (
17
) Quinolone Quinolone2008 Sitaoxacin (
18
) Fluoroquinolone Quinolone2009 Antooxacin (
19
)
c
Fluoroquinolone Quinolone2009 Besioxacin (
20
) Fluoroquinolone Quinolone
Abbreviation: NP, natural product.
a
First member of a new antibiotic class approved for human use underlined. Please note that pleuromutilin derivatives had been previously used in animal health.
132b
For topical use only.
c
Jointly developed by the Shanghai Institute of Materia Medica and Anhui Global Pharmaceutical and approved for use in China in 2009.
Antibiotics in the clinical pipeline in 2011
MS Butler and MA Cooper
414
The Journal of Antibiotics
 
addition to showing activity against Gram-positive bacteria, thesemacrolactones also function against multi-drug-resistant tuberculosis(TB) strains through the same mechanism.
Phase-II trials
In December 2009, Nanotherapeutics (Alachua, FL, USA) acquiredramoplanin (
30
) from Oscient Pharmaceuticals, a company under-going bankruptcy proceedings that had in turn licensed the NorthAmerican rights from Vicuron (Figure 5).
Ramoplanin (
30
), whichis the abbreviation commonly used for ramoplanin-A
2
, has beenevaluated in phase-II trials for the treatment of 
C. difficile
-associateddiarrhea, with plans to undertake phase-III trials.
The ramoplaninlipopeptide antibiotic complex produced by 
Actinoplanes
sp. was firstdescribed by Gruppo Lepetit S.p.A. in 1984,
with structuresreported in 1989.
Ramoplanin (
30
) has been shown to bind tothe peptidoglycan intermediate Lipid-II, which disrupts bacterial cellwall synthesis, causing bacterial cell death.
An X-ray structure of ramoplanin (
30
) in the presence of detergents showed that
30
formsan intimate and highly amphipathic dimer, which allowed a model of 
30
binding to Lipid-II to be proposed.
GSK1322322 (
34
),
which is being developed by GlaxoSmithK-line (GSK, Brentford, UK), has recently completed a phase-II trial foracute bacterial skin and skin structure infections (ABSSSis).
As wellas possessing potent activity against methicillin-resistant
Staphylococ-cus aureus
(MRSA), this compound also shows activity against therespiratory pathogens
Haemophilus influenzae
and
Streptococcus pneu-moniae
. GSK1322322 (
34
) targets bacterial peptide deformylase, ametallo-hydrolase enzyme that catalyzes the removal of the formylgroup from the
-terminal methionine following translation.
BB83698 (
47
) (Oscient)
and LBM-415 (
48
) (Novartis, Basel,Switzerland)
were the first peptide deformylase inhibitors toreach phase-I trials, but no further development of either compound
HNONHOHNNHOHOHNOOHNOONHOHNCO
2
HOH
2
NOCNHONHOHO
2
CNH
2
ONHHHOOOHSH
3
CNHNNHOOHNHNNH
2
OOHO
2
CHO
2
COretapamulin (
3
)daptomycin (
2
)NSOHOHHOHONN+Nbiapenem (
4
)NSOHOHHOHONHNHOOHOertapenem (
5
)OSNHONHNHOHHHOSNH
2
O Odoripenem (
6
)HOHHHNOHOONNSNSOOOOtebipenem pivoxil (
7
)NSOHNHONSNH
2
NOHONONOOOOceftobiprole medocaril (
8
)NSHNHSONNSNONHSNPOHHOON
+
HHCONH
2
OHOOOH NOHNOHHNNHOtigecycline (
11
)ceftaroline fosamil (
9
)OSSHOHOSOOOOCH
3
OOONNNNOHONHOOOOOOOOHOHOHOHOOHHONHHNNHHNOClClNHHNOOHNHNNHO OOtelithromycin (
10
)OHOHHOONH
2
H
2
O
3
PNHtelavancin (
12
)OOOH
Figure 1
Structures of NP-derived antibiotics launched since 2000.
Antibiotics in the clinical pipeline in 2011
MS Butler and MA Cooper
415
The Journal of Antibiotics

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