Low-dose antibiotics

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Low-dose antibiotics: current status and outlook for the future
Nosanchuk, Joshua D.; Lin, Jun; Hunter, Robert P.; Aminov, Rustam
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10.3389/978-2-88919-355-4
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2014
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Nosanchuk, J. D., Lin, J., Hunter, R. P., & Aminov, R. (Eds.) (2014). Low-dose antibiotics: current status and
outlook for the future. Frontiers Media SA. Frontiers Research Topics https://doi.org/10.3389/978-2-88919-355-4

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LOW-DOSE ANTIBIOTICS: CURRENT
STATUS AND OUTLOOK FOR THE
FUTURE
Topic Editors
Joshua D. Nosanchuk, Jun Lin,
Robert P. Hunter and Rustam I. Aminov
MICROBIOLOGY PUBLIC HEALTH
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December 2014 | Low-dose antibiotics: current status and outlook for the future | 1
LOW-DOSE ANTIBIOTICS:
CURRENT STATUS AND
OUTLOOK FOR THE FUTURE
Topic Editors:
Joshua D. Nosanchuk, Albert Einstein College of Medicine, USA
Jun Lin, The University of Tennessee, USA
Robert P. Hunter, Parnell Pharmaceuticals, USA
Rustam I. Aminov, Technical University of Denmark, Denmark
Antimicrobial therapy is a key factor in our success against pathogens poised to ravage at risk
or infected individuals. However, we are currently at a watershed point as we face a growing
crisis of antibiotic resistance among diverse pathogens. One area of intense interest is the
impact of the application of antibiotics for uses other than the treatment of patients and the
association with such utilization with emerging drug resistance. This Research Topic “Low-
dose antibiotics: current status and outlook for the future” in Frontiers in Microbiology:
Antimicrobials, Resistance and Chemotherapy details various aspects of the wide ranging
effects of antimicrobial therapy from areas such as the regulation of host responses to
modulation of bacterial virulence factors to acquisition of antibiotic resistance genes.
December 2014 | Low-dose antibiotics: current status and outlook for the future | 2
Table of Contents
05 Low-Dose Antibiotics: Current Status and Outlook for the Future
Joshua D. Nosanchuk, Jun Lin, Robert P. Hunter and Rustam I. Aminov
07 Biotic Acts of Antibiotics
Rustam I. Aminov
23 Antivirulence Activity of Azithromycin in Pseudomonas Aeruginosa
Francesco Imperi, Livia Leoni and Paolo Visca
30 Responses of Pseudomonas Aeruginosa to Antimicrobials
Yuji Morita, Junko Tomida and Yoshiaki Kawamura
38 Biofilm Formation of Clostridium Perfringens and its Exposure to Low-Dose
Antimicrobials
Audrey Charlebois, Mario Jacques and Marie Archambault
49 The Impact of Antifungals on Toll-Like Receptors
Mircea R. Mihu, Rodney Pattabhi and Joshua D. Nosanchuk
54 Biotic Activity of Ca2+- Modulating Non-Traditional Antimicrobial and -Viral
Agents
Kevin B. Clark
58 Interplay Between Policy and Science Regarding Low-Dose Antimicrobial Use in
Livestock
Amanda C. Sorensen, Robert S. Lawrence and Meghan F. Davis
61 Obesity in the United States – Dysbiosis From Exposure to Low-Dose
Antibiotics?
Lee W. Riley, Eva Raphael and Eduardo Faerstein
69 Antibiotic Alternatives: The Substitution of Antibiotics in Animal Husbandry?
Guyue Cheng, Haihong Hao, Shuyu Xie, Xu Wang, Menghong Dai, Lingli Huang and
Zonghui Yuan
84 Use of Antibiotics as Feed Additives: A Burning Question
Madhab K. Chattopadhyay
87 Benefits and Risks of Antimicrobial Use in Food-Producing Animals
Haihong Hao, Guyue Cheng, Zahid Iqbal, Xiaohui Ai, Hafiz I. Hussain, Lingli Huang,
Menghong Dai, Yulian Wang, Zhenli Liu and Zonghui Yuan
98 Carbadox has Both Temporary and Lasting Effects on the Swine Gut Microbiota
Torey Looft, Heather K. Allen, Thomas A. Casey, David P. Alt and Thaddeus B. Stanton
December 2014 | Low-dose antibiotics: current status and outlook for the future | 3
107 Antibiotics in Canadian Poultry Productions and Anticipated Alternatives
Moussa S. Diarra and François Malouin
122 Perspectives in the Use of Tannins as Alternative to Antimicrobial Growth
Promoter Factors in Poultry
Leandro M. Redondo, Pablo A. Chacana, Johana E. Dominguez and
Mariano E. Fernandez Miyakawa
129 Antibiotic Growth Promoters Enhance Animal Production by Targeting Intestinal
Bile Salt Hydrolase and its Producers
Jun Lin
133 Learning From Agriculture: Understanding Low-Dose Antimicrobials as Drivers
of Resistome Expansion
Yaqi You and Ellen K. Silbergeld
143 Antibiotics Promote Aggregation within Aquatic Bacterial Communities
Gianluca Corno, Manuela Coci, Marco Giardina, Sonia Plechuk, Floriana Campanile
and Stefania Stefani
152 Evolution in Action: Dissemination of tet(X) into Pathogenic Microbiota
Rustam I. Aminov
156 Genomic Interplay in Bacterial Communities: Implicationsfor Growth Promoting
Practices in Animal Husbandry
Piklu Roy Chowdhury, Jessica McKinnon, Ethan Wyrsch, Jeffrey M. Hammond,
Ian G. Charles and Steven P. Djordjevic
December 2014 | Low-dose antibiotics: current status and outlook for the future | 4
EDITORIAL
published:10September2014
doi:10.3389/fmicb.2014.00478
Low-dose antibiotics: current status and outlook for the
future
JoshuaD.Nosanchuk1,2*,JunLin3,RobertP.Hunter4 andRustamI.Aminov5
1DepartmentofMedicine,AlbertEinsteinCollegeofMedicineofYeshivaUniversity,Bronx,NY,USA
2DepartmentofMicrobiologyandImmunology,AlbertEinsteinCollegeofMedicineofYeshivaUniversity,Bronx,NY,USA
3DepartmentofAnimalScience,TheUniversityofTennessee,Knoxville,TN,USA
4ParnellPharmaceuticals,OverlandPark,KS,USA
5SectionforBacteriology,Pathology,andParasitology,NationalVeterinaryInstitute,TechnicalUniversityofDenmark,Frederiksberg,Denmark
*Correspondence:[email protected]
Editedby:
KunihikoNishino,OsakaUniversity,Japan
Reviewedby:
YujiMorita,AichiGakuinUniversity,Japan
ManuelaCoci,NationalResearchCouncil,Italy
Keywords:antibiotics,lowdoseantibiotics,immunomodulatoryeffect,environmentalimpact,growthpromotion,feedadditives
Antimicrobial therapy is a key factor in our success against effector pathways with antimicrobials, Mihu et al. detail how
pathogens poised to ravage at risk or infected individuals. antifungal medications effectively stimulate host responses via
However, we are currently at a watershed point as we face a engagement with toll-like receptors (Mihuet al.,2014).In light
growing crisisofantibiotic resistance amongdiverse pathogens. of the expanding difficulties with drug resistance and a lack of
One area of intense interest is the impact of the application of therapeutics to combat them, Clark presents a cogent call for
antibiotics for uses other than the treatment of patients and pursing Ca2+ modulating strategies where by host Ca2+ home-
the association with such utilization with emerging drug resis- ostasisismodulatedtoblockpathogensfromeffectivelyutilizing
tance. This Research Topic “Low-dose antibiotics: current sta- thisessentialelement(Clark,2013).
tus and outlook for the future” in Frontiers in Microbiology: An important focus in this Research Topic is the use
Antimicrobials, Resistance, and Chemotherapy details various of antibiotics as growth enhancers in animals. Sorensen and
aspectsofthewiderangingeffectsofantimicrobialtherapyfrom colleagues provide key insights into the effects of scientific
areas such as the regulation of host responses to modulation of evidenceonthepolicydecisionsontheuseoflow-doseantimi-
bacterial virulence factors to acquisition of antibiotic resistance crobials in livestock for growth promotion and disease preven-
genes. tion particularly delineating how data have led to the European
Aremarkableandoftenoverlookedfundamentalofantibiotics Union’s ban of low-dose antimicrobials whereas their use in
isthattheyhavebiologicalactivitiesbeyondmicrobialkilling.The the United States of America remains in flux (Sorensen et al.,
host modulatory aspects of macrolides, tetracyclines, and beta- 2014).Thebottomlineisthatthereisanurgentneedtodevelop
lactamsarereviewedbyAminov(2013a)underscoringhow,for policy based on well derived data, with this data being eas-
example,macrolidessuchasazithromycinareroutinelyusedfor ily and widely available to independent parties. The articles by
immunomodulationinpatientswithchronicpulmonarydisease Chengetal.(2014),Chattopadhyay(2014),andHaoetal.(2014)
ratherthanforanantimicrobialeffect.Azithromycinisalsoused all further underscore critically important facets of the contin-
asatoolbyImperietal.todetailhownon-conventionalthinking ued utilization of antibiotics in animal husbandry. Looft and
about regulating virulence factors or modifying host inflamma- colleagues detail their research on how the use of the in-feed
tory cascades are useful to combating major pathogens such as antibiotic carbadox cases dramatic short- and long-term effects
Pseudomonas aeruginosa (Imperi et al., 2014). Along this line, onthecompositionofporcinegutmicrobiota(Looftetal.,2014).
Morita and colleagues carefully detail the pleotropic responses Diarra and Malouin specifically describe the impact of antibi-
ofP.aeruginosatosub-therapeuticlevelsofseveralantibacterials otics in Canadian poultry production and describe the use of
andproposeavenuestopursuetocombatthispathogen,suchas alternatives, such as bioactive molecules from cranberries, that
developingeffluxpumpinhibitors(Moritaetal.,2014).Intheir shouldnotdriveantibioticresistance(DiarraandMalouin,2014).
article, Charlebois et al. show Clostridium perfringens biofilm Similarly,Rendondoetal.providethoughtfulinsightsintotheuse
can be regulated by certain antibiotics at low concentrations oftannins inlieu ofantibiotics for improving health in poultry
(Charleboisetal.,2014).Forexample,lowdosebacitracinsignif- (Redondo et al., 2014). Lin details that the effective of antibi-
icantly enhances biofilm formation whereas low dose penicillin oticsasgrowthpromotersislinkedtodecreasedactivitiesofbile
reducesbiofilm.Thisworkunderscoreshowthereareuntoward salt hydrolase, which thus makes targeting this enzyme directly
effects that are not predictable when antimicrobials are admin- a promising method for removing antibiotics for use as growth
istered at low concentrations. Providing a view on specific host enhancers(Lin,2014).
www.frontiersin.org September2014|Volume5|Article478|5
Nosanchuketal. Broadimpactoflow-doseantibiotics
You and Silbergeld critically discuss the effects of Corno,G.,Coci,M.,etal.(2014).Antibioticspromoteaggregationwithinaquatic
antimicrobials as drivers of resistome expansion (You and bacterialcommunities.Front.Microbiol.5:297.doi:10.3389/fmicb.2014.00297
Silbergeld,2014),amajorsecondaryeffectduetoenvironmental Diarra, M. S., and Malouin, F. (2014). Antibiotics in Canadian poul-
try productions and anticipated alternatives. Front. Microbiol. 5:282. doi:
pollution.Theeffectsofantibioticspermeatingourenvironment
10.3389/fmicb.2014.00282
are highlighted by Conro and colleagues who present their
Hao,H.,Cheng,G.,etal.(2014).Benefitsandrisksofantimicrobialuseinfood-
findingsthatthepresenceofantibioticsinaquaticenvironments producinganimals.Front.Microbiol.5:288.doi:10.3389/fmicb.2014.00288
can induce co-aggregation of bacterial species as an effective Imperi, F., Leoni, L., et al. (2014). Antivirulence activity of azithromycin in
mechanism to combat the effects of the antimicrobials (Corno Pseudomonas aeruginosa. Front. Microbiol. 5:178. doi: 10.3389/fmicb.2014.
00178
et al., 2014), which can lead to extensive resistance through the
Lin,J.(2014).Antibioticgrowthpromotersenhanceanimalproductionbytarget-
transferofresistancegenesamongtheseaggregatedbacteria.Itis ingintestinalbilesalthydrolaseanditsproducers.Front.Microbiol.5:33.doi:
asmallleapforthesemicrobestothenimpacthumansandother 10.3389/fmicb.2014.00033
organisms.Aminovprovidestheexampleoftherampantuseof Looft, T., Allen, H. K., et al. (2014). Carbadox has both temporary and
lasting effects on the swine gut microbiota. Front. Microbiol. 5:276. doi:
tetracyclinesfornon-medicalpurposesasdrivingthepenetration
10.3389/fmicb.2014.00276
of tet(X) into pathogenic microbial communities (Aminov,
Mihu, M.R.,Pattabhi, R., et al. (2014).Theimpact ofantifungals ontoll-like
2013b).Chowdhuryandcolleagueseloquentlydiscusstheimport receptors.Front.Microbiol.5:99.doi:10.3389/fmicb.2014.00099
ofsurveillancestrategiesforcriticallyelucidatingtheemergence Morita, Y., Tomida, J., et al. (2014). Responses of Pseudomonas aeruginosa to
ofdrugresistantpathogensinthecontextoflow-doseantibiotic antimicrobials.Front.Microbiol.4:422.doi:10.3389/fmicb.2013.00422
Redondo, L. M., Chacana, P. A., et al. (2014). Perspectives in the use of tan-
useinanimalhusbandry(RoyChowdhuryetal.,2014).
ninsasalternativetoantimicrobialgrowthpromoterfactorsinpoultry.Front.
In summary, the articles within this Research Topic serve as
Microbiol.5:118.doi:10.3389/fmicb.2014.00118
a “call to arms” for scientists, policy makers and the public to Roy Chowdhury, P., McKinnon, J., et al. (2014). Genomic interplay in bac-
be increasingly vigilant about the use of antimicrobials, partic- terial communities: implications for growth promoting practices in animal
ularlyinlow-doseorwheretheycanbecomewidespreadinthe husbandry.Front.Microbiol.5:394.doi:10.3389/fmicb.2014.00394
Sorensen,A.C.,Lawrence,R.S.,etal.(2014).Interplaybetweenpolicyandscience
environment,inordertomaintainourcapacitytoeffectivelycare
regardinglow-doseantimicrobialuseinlivestock.Front.Microbiol.5:86.doi:
forindividualswithinfectiousdiseases.Thearticlesalsoprovide 10.3389/fmicb.2014.00086
newconceptsforapproachesforthedevelopmentofantimicro- You,Y.,andSilbergeld,E.K.(2014).Learningfromagriculture:understanding
bialsaswellasfornovelgrowthenhancersfortheuseinanimal low-dose antimicrobials as drivers of resistome expansion. Front. Microbiol.
5:284.doi:10.3389/fmicb.2014.00284
husbandry.
ConflictofInterestStatement:Theauthorsdeclarethattheresearchwascon-
REFERENCES ductedintheabsenceofanycommercialorfinancialrelationshipsthatcouldbe
Aminov, R. I. (2013a). Biotic acts of antibiotics. Front. Microbiol. 4:241. doi: construedasapotentialconflictofinterest.
10.3389/fmicb.2013.00241
Aminov,R.I.(2013b).Evolutioninaction:disseminationoftet(X)intopathogenic Received:12August2014;accepted:25August2014;publishedonline:10September
microbiota.Front.Microbiol.4:192.doi:10.3389/fmicb.2013.00192 2014.
Charlebois,A.,Jacques,M.,andArchambault,M.(2014).Biofilmformationof Citation:NosanchukJD,LinJ,HunterRPandAminovRI(2014)Low-doseantibi-
Clostridium perfringens and its exposure to low-dose antimicrobials. Front. otics:currentstatusandoutlookforthefuture.Front.Microbiol.5:478.doi:10.3389/
Microbiol.5:183.doi:10.3389/fmicb.2014.00183 fmicb.2014.00478
Chattopadhyay, M. K. (2014). Use of antibiotics as feed additives: a ThisarticlewassubmittedtoAntimicrobials,ResistanceandChemotherapy,asection
burning question. Front. Microbiol. 5:334. doi: 10.3389/fmicb.2014. ofthejournalFrontiersinMicrobiology.
00334 Copyright©2014Nosanchuk,Lin,HunterandAminov.Thisisanopen-accessarti-
Cheng, G., Hao, H., et al. (2014). Antibiotic alternatives: the substitu- cledistributedunderthetermsoftheCreativeCommonsAttributionLicense(CCBY).
tion of antibiotics in animal husbandry? Front. Microbiol. 5:217. doi: The use, distribution or reproduction in other forums is permitted, provided the
10.3389/fmicb.2014.00217 originalauthor(s)orlicensorarecreditedandthattheoriginalpublicationinthis
Clark,K.B.(2013).BioticactivityofCa2+-modulatingnontraditionalantimicro- journaliscited,inaccordancewithacceptedacademicpractice.Nouse,distributionor
bialand-viralagents.Front.Microbiol.4:381.doi:10.3389/fmicb.2013.00381 reproductionispermittedwhichdoesnotcomplywiththeseterms.
FrontiersinMicrobiology|Antimicrobials,ResistanceandChemotherapy September2014|Volume5|Article478|6
REVIEWARTICLE
published:19August2013
doi:10.3389/fmicb.2013.00241
Biotic acts of antibiotics
RustamI.Aminov*
FacultyofMedicalSciences,UniversityoftheWestIndies,Kingston,Jamaica
Editedby: Biological functions of antibiotics are not limited to killing. The most likely function of
JunLin,TheUniversityofTennessee, antibiotics in natural microbial ecosystems is signaling. Does this signaling function of
USA
antibioticsalsoextendtotheeukaryotic–inparticularmammalian–cells?Inthisreview,
Reviewedby:
the host modulating properties of three classes of antibiotics (macrolides, tetracyclines,
JoseL.Martinez,CentroNacionalde
andβ-lactams)willbebrieflydiscussed.Antibioticscanbeeffectiveintreatmentofabroad
Biotecnología,Spain
RafaelCanton,HospitalUniversitario spectrum of diseases and pathological conditions other than those of infectious etiology
RamonyCajal,Spain and,inthiscapacity,mayfindwidespreadapplicationsbeyondtheintendedantimicrobial
*Correspondence: use.Thisuse,however,shouldnotcompromisetheprimaryfunctionantibioticsareused
RustamI.Aminov,FacultyofMedical
for.Thebiologicalbackgroundforthisinter-kingdomsignalingisalsodiscussed.
Sciences,UniversityoftheWest
Indies,TeachingandResearch Keywords:tetracyclines,macrolides,β-lactam,inflammation,respiratory,cardiovascular,neuroprotection,cancer
Complex,BlockA,RoomA206,Mona
Campus,Kingston7,Jamaica
e-mail:rustam.aminov@uwimona.
edu.jm
INTRODUCTION of their activities, including the direct interaction of antibiotics
We are all familiar with the use of antibiotics for treatment of withthehostcellsaswellasindirect,throughthemodulationof
infectiousdiseases.Butantibioticsdonotonlykillbacteria,their microbiotaand, correspondingly, microbialmetabolites, macro-
original role possibly involved signaling functions (Davies etal., molecules,andotherbiologicallyactivecomponentsofmicrobiota
2006; Linaresetal.,2006;Yimetal.,2006,2007; Martínez,2008; thataffectthehost.Andfinally,itisintriguingtorecognizehow
Aminov,2009;Romeroetal.,2011).Thesefunctions,usuallyper- manymoleculartargetsforantibioticsareinthehumanbody.Isit
formedatlowerconcentrations,aredifferentfromthoseleadingto bychancethattheyhavesuchpleiotropicpropertiesthatareaffect-
celldeath,andtheyarerealizedthroughdifferentsetsofmolecular ingalmosteveryorganorsysteminthehumanbody?Onlythree
targetsinthecell.Whilemanyaspectsofthiscommunicationin classesof antibioticsarecoveredinthisreviewbecauseof space
themicrobialworldremainelusive,thereisalargebodyofinfor- restraints.Thesearethemacrolides,tetracyclines,andβ-lactams.
mationregardingthesignalingeffectsoflow-doseantibioticson Forthesamereason,onlyfewmostimportantexamplesforeach
humansandanimalsbeyondtheintendedantimicrobialactivities. antibioticclassandforeachgroupofdiseasesaregiven.Theseare
Thus the intention of this article is to undertake an interdisci- followedbyadiscussionofvariousimplicationsoftheeffectsand
plinarycoverageof andfamiliarizebiologistswiththisaspectof consequencesofthenon-antimicrobialantibioticuse.
non-antimicrobialantibioticuseinclinicalresearchandpractice.
Theresultscoveredinthisreviewhavebeencollectedinvarious MACROLIDES
animal models, tissue cultures, and pre-clinical and clinical tri- There are many examples of antibiotic signaling effects on the
als,withlittleornoinvolvementofmicrobiology,and,therefore, host beyond the intended antimicrobial activity. The use of
mighthaveescapedtheattentionofmicrobiologists.Ibelievethis macrolides for treatment of non-infectious diseases has the ear-
interdisciplinarycoverageishighlyimportanttoclosethegapin liest history among other antibiotics. A considerable amount of
non-antimicrobialuseofantimicrobialsforanumberofreasons. informationregardingthetherapeuticpotentialofmacrolidesfor
Firstofall,itisthespecificsofthistypeoftherapy,withtheuse non-antimicrobialusehasbeencollectedbeginningfromthelate
of low-dose antibiotics for very extended periods of time mea- 1980s. Since then, a great number of animal experiments have
suredinweeks,months,andevenyears.Second,whileinclinical beenperformed,manyrepresentativesof thisclassof antibiotics
microbiologyagreatdealofattentionispaidtotheappearanceof havegonethroughclinicaltrials, andanumberof drugsinthis
antibioticresistanceasasideeffectofantibiotictherapy,thisaspect grouphavebeenapprovedandarecurrentlycommonlyusedin
hashadarelativelylowpriorityandhasbeenlargelyoverlookedin clinicalpracticefornon-antimicrobialpurposes.
thelow-doselong-termantibiotictreatmenttrials.Anotheraspect Theuseofmacrolideshasbeenespeciallysuccessfulintheman-
thatmayneedmorecarefulconsiderationinthistypeoftherapy agementofvariouschronicrespiratorydiseasesnotonlyintherole
istheroleofcommensalmicrobiota,whichisalsoanimportant of antimicrobial agents but also due to their anti-inflammatory
playerinhumanmetabolismandphysiology.Antibioticsactnot andpro-kineticproperties.Thepositiveeffectoflong-termlow-
onlyonthetargetsinthehumanbodybutalsoonthemicrobiota, doseadministrationoferythromycintopatientswithdiffusepan-
whichistheintegralpartof humanmetabolismandphysiology. bronchiolitiswasdemonstratedbyJapaneseresearchersmorethan
And as we know, the role of commensal microbiota in human twodecadesago,thussuggestingotherthanantimicrobialnature
healthanddiseaseisimmense,affectingalmosteveryaspectofit. of erythromycin action (Kudoh etal., 1987; Nagai etal., 1991).
Thus the antibiotic effects have to be evaluated from both sides From this point, the use of macrolides for non-antimicrobial
www.frontiersin.org August2013|Volume4|Article241|7
“fmicb-04-00241” — 2013/8/16 — 21:17 — page 1 — #1
Aminov Bioticactsofantibiotics
purposeshasbecomeoneofthemainstreamchoicesfortreatment The positive effect of clarithromycin in cardiovascular diseases
ofchronicrespiratorydiseases. maybeduetothealterationofinflammatoryfactorsandmatrix
In cystic fibrosis (CF), the main bacterium associated with metalloproteinases(MMPs).MMPsasapartoftheextracellular
the pulmonary disease is Pseudomonas aeruginosa, which pro- matrixparticipateinanumberofnormalphysiologicalprocesses,
ducesbiofilmsresistanttoantibiotictreatmentwithintheairways which contribute to tissue structure, function, and remodeling,
(Singh etal.,2000). AlthoughP.aeruginosa isnaturallyresistant includingthemyocardium(Spinaleetal.,2013).Boththeexpres-
tomacrolides,theseantibiotics,evenatsubinhibitoryconcentra- sionandactivityof MMPsareregulatedbythetissueinhibitors
tions,cansuppressquorumsensingnecessaryforbiofilmforma- of matrix metalloproteinases (TIMPs), and the MMPs/TIMPs
tion (Tateda etal., 2007). This mechanism possibly contributes balanceiscrucialforthenormalmaintenanceofmyocardialinter-
to the heightened sensitivity of non-susceptible P. aeruginosa stitialhomeostasis. Misbalanceandtheresultinginvolvementof
toward a variety of anti-pseudomonal agents in biofilms when MMPs in disease, however, have been shown for a number of
exposedtomacrolidesatsubinhibitoryconcentrations(Lutzetal., pathologiesspanningfromcancertocardiovasculardiseasesand
2012). In addition, low-dose macrolides display immunomod- toneurodegeneration(Sbardellaetal.,2012).Theprotectiveeffect
ulatory properties influencing cytokine production and altering ofclarithromycininthecaseofautoimmunemyocarditisappears
polymorphonuclearcellfunctions(Schultz,2004).Thisprevents tobeimplementedthroughtheinhibitionoftheMMP-9activity
excessiveuncontrolledinflammationandassociatedtissuedam- (Hishikarietal.,2010).Inthelongrun,however,ashort-termclar-
age.Anotherbenefitofthemacrolideuseinthemanagementof ithromycinadministrationinpatientswithcoronaryheartdisease
CFisthereducedchronicairwayhypersecretion(Tamaokietal., for clearance of suspected infections results in increased risk of
1995). mortality(Gluudetal.,2008).
Treatment of other respiratory diseases such as asthma may Immunosuppressiveactivitiesofmacrolideshavebeenknown
benefit from the dual action of macrolides because asthma is a foralmostfourdecadesnow.Thefirstmacrolidewiththisactiv-
result of interaction of genetic and environmental factors. The ity,rapamycin(alsocalledsirolimus),wasdiscoveredbyBrazilian
presence of Mycoplasma pneumoniae and Chlamydophila pneu- researchersduringascreeningprogramforantifungalcompounds
moniae in asthmatics best identifies the macrolide responsive produced by soil bacteria (Vézina etal.,1975). But its use as an
phenotype because of the antimicrobial and anti-inflammatory antifungalantibiotichasbeenabandonedduetopotentimmuno-
properties of macrolides covering the infection and genetic suppressive and antiproliferative activities. Its antiproliferative
predispositioncontinuum(Goodetal.,2012). actionisrealizedthroughtheformationofanactivecomplexwith
Chronicobstructivepulmonarydisease(COPD)remainsone its cytosolic receptor protein, FKBP12, and targeting of a puta-
of theimportantcausesof morbidity,mortality,andhealth-care tivelipidkinasetermedtargetof rapamycin(TOR;Brownetal.,
costsworldwide(ManninoandBuist,2007). Althoughsmoking 1994; Sabers etal., 1995; Wiederrecht etal., 1995). The loss of
is the most important risk factor for the disease, it also has a TORfunctionleadstotheinhibitionof G1-toS-phaseprogres-
substantialgeneticcomponent(Wainetal.,2012).Pathogenesisin sion in various sensitive cells. The immunosuppressive activity
COPDislargelydrivenbydysregulatedresponsesoftheinnateand of rapamycinisalsorealizedviathesameproteinkinaseinhibi-
adaptiveimmunesystemstotheenvironmentalcuesleadingtoan tion pathway affecting cell-cycle proliferation of lymphoid cells
exaggeratedinflammatoryresponse,whichresultsinpermanent (Abraham,1998).
inflammation, tissue damage, and lung function decline (Hol- The TOR complexes regulate cell growth and metabolism in
lowayandDonnelly,2013).Awell-designed,randomized,1-year response to environmental and intracellular cues and are com-
trialoferythromycin,atadoseof250mgtwicedaily,hasfound prised of two distinct multiprotein complexes: TOR complex 1
asignificantreductioninCOPDexacerbationscomparedtothe (TORC1), which is sensitive to rapamycin, and TORC2, which
placebogroup(Seemungaletal.,2008).Long-termadministration is not (Wullschleger etal., 2006). Dysregulation of these com-
ofazithromycinbyoutpatientswithsevereCOPDhasappearedto plexes is associated with various pathologies, including cancer,
besafeandeffective,withreducedexacerbations,hospitalizations, cardiovasculardiseases,autoimmunity,metabolicdisorders,and
andimprovedqualityoflife(Blasietal.,2010).Anothertrialwith neurodegenerative diseases. Thus rapamycin and its derivatives
a daily azithromycin for 1 year for prevention of exacerbations canbeusedfortreatmentofavarietyofdiseases(Cruzado,2008).
ofCOPDhasdemonstrateddecreasedfrequencyofexacerbations Itisalsopotentiallyusefulfortreatmentofsubstanceabusecon-
andimprovedqualityof lifebuthascausedhearingdecrements ditions, alcohol abuse in particular, since inhibition of TORC1
in a small percentage of subjects (Albert etal., 2011). A recent by rapamycin disrupts alcohol-associated memory reconsolida-
reviewofcontrolledclinicalstudiesfocusingonthepreventionof tion,leadingtoalong-lastingsuppressionofrelapse(Baraketal.,
COPDexacerbationswithlong-termazithromycin,erythromycin, 2013).Currentlyitisapprovedforpreventionoftransplantrejec-
orclarithromycintreatmentsuggeststhatitiseffective,safe,and tion,anditslatestderivative,everolimus,iswidelyusedtoprevent
cost-efficient(Simoensetal.,2013).Otherchronicrespiratorydis- therejectionofheart,lung,kidney,orliverallografts(Gurk-Turner
easesmayalsobetreatedbymacrolides,butbetterdesignedtrials etal., 2012). Since TOR complexes are evolutionary conserved
arenecessarytoconfirmtheirefficacy(SureshBabuetal.,2013). and involved in very fundamental biological processes in the
Novel effects of macrolides on cardiovascular diseases have cell, pharmacologicalinhibitionof TORsignalingbyrapamycin
been discovered recently. In animal models, clarithromycin has increases the lifespan of yeasts and higher eukaryotes (Powers
suppressedthedevelopmentofmyocarditis,cardiacrejection,and etal., 2006). The use of rapamycin in humans as an anti-aging
myocardial ischemia (Nakajima etal.,2010; Suzuki etal.,2012). agentisuncertainbecauseofsideeffects;thisusewillrequirethe
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