Antimicrobial Compounds: Current Strategies and New Alternatives

325 Pages·2014·5.49 MB·English

by  Carlos Olano

Tomás G. Villa
Patricia Veiga-Crespo Editors
Antimicrobial
Compounds
Current Strategies and New Alternatives
Antimicrobial Compounds
Tomás G. Villa Patricia Veiga-Crespo
•
Editors
Antimicrobial Compounds
Current Strategies and New Alternatives
123
Editors
TomásG.Villa Patricia Veiga-Crespo
Faculty ofPharmacy, Department of Biomedical Center
Microbiologyand Parasitology LundUniversity
Universityof Santiago deCompostela Lund
Santiago deCompostela Sweden
Spain
ISBN 978-3-642-40443-6 ISBN 978-3-642-40444-3 (eBook)
DOI 10.1007/978-3-642-40444-3
SpringerHeidelbergNewYorkDordrechtLondon
LibraryofCongressControlNumber:2013951131
(cid:2)Springer-VerlagBerlinHeidelberg2014
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Preface
Since the very beginning, the relationship between humans and microorganisms
has moved between love and hate. People have used bacteria and yeast to man-
ufacture foods, even when they did not know what a microorganism was. Thanks
to bacteria and fungi, we can produce wine, yogurt, beer, or bread. However,
microorganisms have been also sources of illness, chaos, and destruction. For
example,thebubonicplaguesduringtheMiddleAgescausedadramaticdecrease
in the European population. Also, for centuries, doctors, physicians, and even,
wise men treated patients and fought against infections without knowing their
enemies or without having the right weapons.
The development of the initial microscopes allowed to identify the enemies;
the bacteria and fungi could be observed, but not destroyed. Some researchers
were able to find out how microorganisms spread between people and then, they
could isolate the ill from the healthy individuals. The first clear and efficient step
againstinfectionswasthedevelopmentofvaccines.But,whatdidtheyhavetodo
with the ill?
The twentieth century brought light into the darkness. The first drug against
syphiliswasdeveloped,thesalvarsanwasthefirstactiveprincipleabletoattacka
microorganism, Treponema pallidum. Its unique problem was that salvarsan had
arsenic inside and this could originate several side effects in the patients.
When Sir Alexander Flemingwas able tounderstand what was happening in a
contaminated Petri dish, he discovered penicillin, and the Antibiotic Era began
officially. Then someone had the idea that the end of the infection illnesses was
coming. A century and several active principles later, deaths by infections are
almost 25 % of the total deaths per year around the world.
What did happen in the middle? The irrational and bad use of antimicrobial
drugs exerted a selective pressure over microorganisms. Bacteria and fungi
developed different mechanisms to avoid the antimicrobials, and humans with
their bad behavior just selected them.
In the last 20 years, the number of new antimicrobials has been lower and
lower, while the number of resistant microorganisms has become higher and
higher.Theclassictechniquestodevelopnewantimicrobialsbecamelessandless
effective and pharmaceutical companies tried to put their efforts in other fields
with a better ratio of profits, such as stroke injuries, hypertension, and so on.
However, we still need new antimicrobials.
v
vi Preface
The search for new sources of antimicrobials, the design of more efficient
researchpolicies,andtheuseofnewtechnologiesarenowmandatory.Thisisthe
goalofthisbook.Duringthedifferentchapters,thereaderwillbeabletofindout
thelatestadvancesinthedevelopmentofnewantimicrobialdrugstogetherwitha
recapitulation of new potential sources of drugs.
Theaimofthisbookistwofold.Ittriestobeanaccurateandextensivereview
oftheactualstateoftheartinthefieldofantimicrobialresearch,but,ontheother
hand, it also tries to be the initial point for developing new alternatives and
strategies in the fight against resistant microorganisms.
Lund, Sweden Patricia Veiga-Crespo
Santiago de Compostela, Spain Tomás G. Villa
Contents
1 Strategies for the Design and Discovery of Novel Antibiotics
using Genetic Engineering and Genome Mining . . . . . . . . . . . . . 1
Carlos Olano, Carmen Méndez and José A. Salas
2 X-Ray and Neutron Scattering Foundations for the Research
in Antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Daniel Piso
3 Antibacterial, Antiviral and Antifungal Activity of Essential
Oils: Mechanisms and Applications. . . . . . . . . . . . . . . . . . . . . . . 51
Karola Böhme, Jorge Barros-Velázquez, Pilar Calo-Mata
and Santiago P. Aubourg
4 New Antimicrobial Agents of Plant Origin . . . . . . . . . . . . . . . . . 83
Javier Sampedro and Elene R. Valdivia
5 Advances in Beta-Lactam Antibiotics . . . . . . . . . . . . . . . . . . . . . 115
José-Luis Barredo, Gulay Ozcengiz and Arnold L. Demain
6 The Cornerstone of Nucleic Acid-Affecting Antibiotics
in Bacteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
M. Gacto, M. Madrid, A. Franco, T. Soto, J. Cansado
and J. Vicente-Soler
7 Genetic Analysis and Manipulation of Polyene Antibiotic
Gene Clusters as a Way to Produce More Effective
Antifungal Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Michal Letek, Luis M. Mateos and José A. Gil
8 Enzybiotics: The Rush Toward Prevention and Control
of Multiresistant Bacteria (MRB) . . . . . . . . . . . . . . . . . . . . . . . . 215
Patricia Veiga-Crespo, Angeles Sanchez-Perez and Tomás G. Villa
vii
viii Contents
9 New Cell Wall-Affecting Antifungal Antibiotics. . . . . . . . . . . . . . 237
Juan Carlos Ribas, Ángel DurÁn and Juan Carlos G. Cortés
10 Perspectives in the Research on Antimicrobial Peptides. . . . . . . . 269
Miguel Viñas, Francesc Rabanal, Roland Benz,
Teresa Vinuesa and Ester Fuste
11 Glycopeptides and Bacterial Cell Walls. . . . . . . . . . . . . . . . . . . . 285
Fernando Santos-Beneit, Juan F. Martín and Carlos Barreiro
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Introduction
New tools to look within microbial genomes potentially hiding a rich array of
pharmaceuticalsurpriseshasbeendevelopedinrecentyearsandthishasledtothe
discovery of a novel antibiotics that could highlight new treatments for serious
diseases caused by multi-drug-resistant microorganisms.
Undoubtedly, the availability of whole microbial genomes and related
information has opened up many of these new ways for antibiotic hunting. The
greatestbenefit obtainedfromthesenew approacheslies intheabilitytoexamine
several genomes simultaneously, so a potential target can be evaluated against
another,andtheeffectscomparedacrossspecies.Thisissuewasfirstaddressedas
early as 1998 by Allsop (1998), and two years later by Mendez et al. (2000) (for
more information see Chap. 1). In 2002 the topic was again reviewed by Haney
et al. concluding that taken together, these technologies, overlaid within an
established drug discovery program, now affords the opportunity for the identifi-
cation, validation, and process design for high-throughput target mining at
unprecedented volumes and timeframes (Haney et al. 2002).
In this same year Chaker et al. (2002) revisited this topic in a comprehensive
paperthatconcludeswithtwoideasworthofbeingquotedinthisintroduction;one
is that in general, it takes a total of 5–8 years to progress antibiotic candidates
throughdrugdevelopmenttoregulatoryapproval,withasignificantprobabilityof
failure at each stage and two, that concerns the diversity of both target enzymes
and inhibitory molecules. If there are ca 300 broad-spectrum essential potential
target genes, it may be an achievable goal to identify and screen all of them in a
relatively short period of time.
As pointed out by Demain and Sanchez (2009) microbes have made a great
contributiontothewell-beingofmankind.Inadditiontoproducingmanyprimary
metabolites, such as amino acids or vitamins, they are capable of producing sec-
ondary metabolites that has saved millions of lives in the last 80 years, after
introduction of B-lactam antibiotics such as penicillins in the market. Despite the
fact that companies are reluctant to invest in the seeking of new antibiotic sub-
stancesfromavarietyofsources,weneedtomoveonandtrytokeepupwiththis
old tradition plus the designing of new drugs, supported by the pure force of
organic chemistry.
Also, the use of unusual bacterial components as targets for new antibiotics is
startingtoproducegoodresults.ThisisthecaseofLipidII,amembrane-anchored
ix
x Introduction
cell-wallprecursoressentialforbacterialcell-wallbiosynthesis,andthatcanbethe
target for vancomycin, lantibiotics, mannopeptimycins, and ramoplanin; it may
therefore be worth to exploit their potential as new treatments for bacterial
infections(BreukinkanddeKruijff2006).Asfortheexploitationofoldmicrobial
groups known since the very beginning of the antibiotic era, one has to keep in
mind the marine actinomycetes that constitute a fabulous group for the discovery
ofapleyadofnewantibiotics.QuotingFenicalandJensen(2006)Membersofthe
genus Salinispora have proven to be a particularly rich source of new chemical
structures,includingthepotentproteasomeinhibitorsalinosporamideA,andother
distinct groups are yielding new classes of terpenoids, amino acid–derived
metabolites and polyene macrolides.
AnexampleoftheaboveisshownintheworkofHasteandco-workers(Haste
et al. 2010). Their work highlighted the discovery of the streptogramin etamycin
produced by an actinomycete species isolated from the coast of Fiji that demon-
strated potent activity against HA- and CA-MRSA with MICs as low as 1–2 mg
l-1 against HA- and CA-MRSA strains and was found to be non-cytotoxic at
concentrationsmorethan20-foldaboveMIC.Byallmeansthisnewantibioticwas
comparable to the mighty vancomycin and also conferred significant protection
from mortality in a murine model of systemic lethal MRSA infection. These data
emphasize once more the utility of the marine environment as a yet-to-be-dis-
covered source of antibiotics.
The combinatorial synthesis ofantibiotics has tobe necessarily addressed here
(Weissman and Leadlay 2005) since the bacterial multienzyme polyketide syn-
thases (PKSs) produce a diverse array of products that have been developed into
medicines, including antibiotics and anticancer agents. So far and as indicated by
these authors ‘‘directed engineering of modular PKSs has resulted in the produc-
tion of more than 200 new polyketides, but key challenges remain before the
potential of combinatorial biosynthesis can be fully realized.’’
The search for healing principles in plants is an ancient idea and people ever
sincetheverybeginningofcivilizationhavedugintoallkindofplantstogetrelief
fromtheir painsby means ofinfusionsand the like.Infact, thereis evidence that
Neanderthals living 60,000 years ago already used plants for the treatment of
diseases. It is estimated that there are up to 500,000 species of plants on Earth
(Borris1996;Murphy1999).Onlyasmallpercentage(ca9 %)oftheseareusedas
foods while the rest are either kept for their pharmaceutical potential or are poi-
sonous to humans or animals. Hippocrates mentioned up to 300–400 medicinal
plants and many of them have passed to our use thanks to the Arabs and monks
throughout the Middle Age.
Of particular interest are the so-called bioenhancers of plant origin. They are
phytomoleculescapableofenhancingbioavailabilityofagivendrugwithwhichit
iscombined.ThetermbioavailabilityenhancerwasfirstcoinedbyIndianScientists
attheRegionalResearchLaboratory,Jammu(RRL,nowknownasIndianInstitute
of Integrative Medicine) discovered and scientifically validated piperine as the
world’s first bioavailability enhancer in 1979 (for a comprehensive review see
(Dudhatra et al. 2012)). There are many ways by which bioavailability may be