Bioprospecting Sponge-Associated Microbes for Antimicrobial Compounds

66 Pages·2016·2.23 MB·English

marine drugs
Review
Bioprospecting Sponge-Associated Microbes for
Antimicrobial Compounds
AnakAgungGedeIndraningrat1,2,HaukeSmidt1andDetmerSipkema1,*
1 LaboratoryofMicrobiology,WageningenUniversity,Dreijenplein10,Wageningen6703HB,
TheNetherlands;[email protected](A.A.G.I.);[email protected](H.S.)
2 DepartmentofBiology,FacultyofMathematicsandScienceEducation,InstitutKeguruandanIlmu
PendidikanPersatuanGuruRepublikIndonesia(IKIPPGRI)Bali,Jl.SerojaTonja,Denpasar80238,Indonesia
* Correspondence:[email protected];Tel.:[phone]
AcademicEditor:KirstenBenkendorff
Received:29February2016;Accepted:26April2016;Published:2May2016
Abstract: Sponges are the most prolific marine organisms with respect to their arsenal of
bioactive compounds including antimicrobials. However, the majority of these substances
are probably not produced by the sponge itself, but rather by bacteria or fungi that are
associated with their host. This review for the first time provides a comprehensive overview
of antimicrobial compounds that are known to be produced by sponge-associated microbes.
We discuss the current state-of-the-art by grouping the bioactive compounds produced by
sponge-associated microorganisms in four categories: antiviral, antibacterial, antifungal and
antiprotozoalcompounds. Basedoninvitroactivitytests,identifiedtargetsofpotentantimicrobial
substances derived from sponge-associated microbes include: human immunodeficiency virus 1
(HIV-1) (2-undecyl-4-quinolone, sorbicillactone A and chartarutine B); influenza A (H1N1)
virus (truncateol M); nosocomial Gram positive bacteria (thiopeptide YM-266183, YM-266184,
mayamycinandkocurin);Escherichiacoli(sydonicacid),Chlamydiatrachomatis(naphthaceneglycoside
SF2446A2); Plasmodium spp. (manzamine A and quinolone 1); Leishmania donovani (manzamine
A and valinomycin); Trypanosoma brucei (valinomycin and staurosporine); Candida albicans and
dermatophyticfungi(saadamycin,5,7-dimethoxy-4-p-methoxylphenylcoumarinandYM-202204).
Thirty-fivebacterialand12fungalgeneraassociatedwithspongesthatproduceantimicrobialswere
identified, with Streptomyces, Pseudovibrio, Bacillus, Aspergillus and Penicillium as the prominent
producers of antimicrobial compounds. Furthemore culture-independent approaches to more
comprehensivelyexploitthegeneticrichnessofantimicrobialcompound-producingpathwaysfrom
sponge-associatedbacteriaareaddressed.
Keywords: antimicrobialcompounds;sponges;sponge-associatedmicrobes
1. Introduction
Antimicrobial resistance (AMR) is an emerging global threat, decreasing the possibilities
for prevention and treatment of infectious diseases caused by viruses, bacteria, parasites and
fungi [1,2]. A global surveillance report by the World Health Organization (WHO) [2] indicated
an increase of morbidity and mortality of infectious diseases due to AMR, which could lead to a
world-wide economic loss of up to 100 trillion US dollars (USD) in 2050 as the result of a 2%–3%
reduction in the gross domestic product (GDP) [1]. A conservative estimation is that AMR now
annuallyattributesto700,000deathsglobally,withapotentialleapto10millionin2050[1]. AMR
is a response of microorganisms against antimicrobial compounds, which can arise via several
mechanismssuchaschromosomalmutations[1],bindingsitemodifications[2]orhorizontaltransfer
ofgenesconferringresistance[3]. ForseveralpathogenicbacteriasuchasStaphylococcusaureus[4],
Mar.Drugs2016,14,87;doi:10.3390/md14050087 www.mdpi.com/journal/marinedrugs
Mar.Drugs2016,14, 87 2of66
Pseudomonasaeruginosa[1,5],andMycobacteriumtuberculosis[6],theemergenceofmultidrugresistant
(MDR)strainshasbeenreported,whichmakeinfectionswiththesestrainsincreasinglydifficultto
treatwithcurrentlyavailableantibiotics[3].
In the context of the arms race between humans and infectious agents, the discovery and
development of new types of antimicrobial compounds with pronounced bioactivity and clinical
significanceareurgent[4,5]. Theeffortstomodifyexistingdrugsareoftennoteffectivetoovercome
themutationrateofpathogensanddonotleadtotheintroductionofnewclassesofantimicrobial
compounds [6]. The terrestrial environment has been the main focus of microbial-derived drug
discoverysincethefirstreportonPenicillinin1929[7],followedbytheboomingofnewclassesof
antibioticsin1960s[8].Althoughnovelantimicrobialsarestillbeingdiscoveredfromthesoilniche,e.g.,
turbomycinAandB[9]andteixobactin[10],thereareissueswithde-replication,whichsignificantly
reducesthediscoveryrateofnewcompoundsfromheavilyscreenedenvironments[11].
Incomparisonwithsoils,themarineenvironmenthasbeenlargelyneglectedfordiscoveryof
antibiotics until recently, mainly because of accessibility issues, but yet hold a huge biodiversity
and potential novelty of antimicrobial compounds [12]. Of many marine organisms, sponges
(phylum Porifera) are considered as the most prolific source of therapeutic compounds as these
animalsharbouralargevarietyofsecondarymetabolites,manyofwhicharebeneficialforhuman
healthpurposes[13–17]. The“SupplyIssue”isthemainobstacletoexploitthebiologicalactivityof
sponges’metabolitessincealargequantityofbiomaterialisrequiredforexperimentalpurposes[13].
Interestingly,inrecentyearsanincreasingnumberofstudieshighlightedthatmanyactivesubstances
from sponges are of bacterial origin due to similarity to chemical structures found in terrestrial
microorganisms[13–15]. Furthermore,severalstudieshavereportedawidediversityofantimicrobial
activitiesfromsponge-associatedmicrobes,whichmakethesemicrobialcommunitiesavaluablesource
fornovelantimicrobials[14,16–20].
This review highlights the current knowledge of antimicrobial compounds produced by
sponge-associatedmicrobes. Ourdefinitionof“antimicrobial”isnotlimitedtoantibacterialagents,
butalsoincludescompoundsactiveagainstviruses,fungiandinfectiousprotozoa. Foreachofthe
fourbiologicalactivities,afewsubstancesarehighlightedbecauseoftheirhighactivity,alongwith
the most complete overview to date of other known compounds with antimicrobial activity from
sponge-associatedmicroorganisms. Tocomparedifferentbioactivecompoundsandcrudeextracts,
inhibitory concentrations of substances reviewed have been as much as possible expressed in the
sameunit(µg/mL).Originalarticlesuseminimuminhibitoryconcentrations(MIC),halfmaximum
inhibitoryconcentrations(IC )andtheconcentrationofadrugthatgivethehalf-maximalresponse
50
(EC ). Astheyarenoteasilyconverted,westickedtotheoriginalmeasures.
50
Moreover,weanalyzedthedistributionofbacterialandfungalgeneraassociatedwithsponges
that have been reported to produce antimicrobial compounds to identify the most prolific genera.
In addition, the potential for application of metagenomics to complement culture-dependent
antimicrobialscreeningstrategiesisalsodiscussed.
2. AntiviralCompounds
Newantiviralcompoundsareneededduetotheincreasedoccurrenceofdiseasescausedbyviral
infectionsandbecauseofantiviralescapestrategies[21]. Marineorganisms,andspongesinparticular,
havebeenshowntobeavaluablesourceforantivirals. Forexample,thediscoveryofthenucleosides
spongothymidineandspongouridinefromthespongeTethyacryptawasthebasisforthecompound
Ara-A(vidarabine)thatisactiveagainsttheherpessimplexvirus[21–24].
Screening of sponge-associated microbes yielded several prospective anti-HIV-1 (human
immunodeficiency virus-1) compounds (Table 1 and Figure 1). Bultel-Poncé et al. [25] isolated
Pseudomonassp. 1531-E7fromthemarinespongeHomophymiasp. resultinginthediscoveryofthe
antiviralcompound2-undecyl-4-quinolone(1)(Figure1). ThecompoundhadanIC concentration
50
aslowas10´3µg/mLinvitroagainstHIV-1. Bringmannetal.[26]elucidatedthechemicalstructure
Mar. Drugs 2016, 14, 87 3 of 79
sorbicillactone A (2) which was isolated from Penicillium chrysogenum, a fungus associated with the
sponge Ircinia fasciculata. Sorbicillactone A displayed cytoprotective effects on HIV-1-infected cells of
the human cell line H9 at concentrations of 0.1–1 µg/mL. In addition, in vitro testing using H9 cells
indicated that sorbicillactone A reduced the appearance of the HIV-1 protein up to 70% at a
concentration of 0.3 µg/mL [26]. The sponge-associated fungus Stachybotrys chartarum MXH-X73
produces the compound stachybotrin D (3), which exhibited anti-HIV-1 activity by targeting reverse
transcriptase [27]. At EC50 concentrations from 2.73 µg/mL to 10.51 µg/mL, stachybotrin D was active
not only against the wild type HIV-1 but also against several non-nucleoside reverse transcriptase
inhibitor (NNRTI) resistant HIV-1 strains. Li et al. [28] reported identification of three other
Mar.Drugs2016,14, 87 3of66
anti-HIV-1 compounds from Stachybotrys chartarum: chartarutine B, G, and H. Of these three
chartarutine compounds, chartarutine B (4) showed the lowest concentration that resulted in 50%
oinfhsiobribtiiocnil laocft oHnIeVA-1 (2(I)Cw50h oicfh 1w.8a1s µisgo/lmatLe)d, ffroolmlowPeedni cbilyli ucmhacrhtaryrusotgineen uGm ,(aICf5u0 nogfu s2.a0s5s oµcgia/mteLd) wainthd
tchhearstpaoruntgineeI rHci n(IiCa5f0a socfi c2u.0la5t aµ.g/SmorLb)i,c riellsapcetoctniveeAly.d isplayed cytoprotective effects on HIV-1-infected
cellsSopfothnegeh-uamssoanciacteeldl lminiecrHob9east hcaovnec eanlstora btieoenns fooufn0.d1 –to1 pµrgo/dmuLce. Ianntaid-idnfitluioenn,zian cvoitmroptoeustnidnsg (uTsaibnlge
H1)9. Zchelalos ient dali.c [a2t9e]d etlhuacitdsaotrebdi c1i4ll ancetwon iesoAprreendyulcaeteddt chyecalophpeexaarnaonlcse coofinthede aHsI tVr-u1npcarotetoelisn Au-pNt ofr7o0m% thaet
aspcoonngcee-natsrsaoticoianteodf 0fu.3nµgug/s mTrLun[2ca6t]e.llTah aengspusotnatgae, -aansdso tchiaesteed cofumnpgouusnSdtsa cwhyebreo ttreysstecdha irnt avriutrmo aMgaXiHns-tX t7h3e
pinroflduuencezsa thAe c(oHm1Npo1u) nvdirsutsa.c hTyrbuontcrainteDols( 3)C,,w Eh icahndex hMib idteisdpalanytei-dH IbVio-1acatcitviivtiyt yabgyaitnasrtg eHti1nNg1re, vweristhe
ttrraunnsccartiepotal sMe[ 2(75]). bAetinEgC 5t0hceo mncoesntt rpaotitoennst firnohmib2it.7o3r, µags/ smhLowton1 0b.y5 1itµsg I/Cm50L v,astlauceh oyfb o2t.r9i1n µDgw/masLa. cTtihvies
ninohtiobnitloyrya gcaoinncsetnthtreatwioinld wtyaps ealHmIoVs-t1 sbixu tfoallsdo loagwaeirn stthasenv tehraatl noof nth-neu pcolesoitsiivdee croenvterrosle otsrealntasmcriipvitra saet
i1n4h.5ib2i tµogr/(mNLN. RTTruI)nrceastisetoaln MtH wIVa-s1 psrteradiincste.dL iteot bale. [a2c8ti]vree paot rttheed liadteen sttifiagcaet ioofn thoef tvhirreues oitnhfeerctaionnti,- HlikIVe-ly1
cdoumripnogu tnhde sasfsroemmbSlyt aocrh yrbeoletraysse cshteaprt aorfu tmhe: vcihraiornta r[2u9ti]n deuBe ,toG r,easnemdbHla.nOcef othf ethsee tinhhreibeitcihoanr tpaartutetirnnes
coobmseprvoeudn dfos,r cnheaurrtaamruitninideasBe-(i4n)hsibhiotowre ddruthges, loe.wg.e, sztacnoanmceivnitrr aatniodn otshealttamreisvuilrt e[d30i]n. I5n0 a%ddinithioibni,t itohne
opfreHsIeVn-c1e (oICf 5a0 cohflo1.r8in1eµ agt/ommL i)n, ftohlelo cwheedmbicyalc hstarrutcatruurtein oef Gtr(uIcCa5n0toeofl2 .M05 iµs go/f mpaLr)tiacnudlacrh ianrttearreustt insienHce
(hICal5o0goefn2a.t0io5nµ ogf/tmenL e),nrheasnpceecst ibvieolay.ctivity of a given compound [31,32].

FFiigguurree 11.. CChheemmiiccaall ssttrruuccttuurreesso offt htheea nantitviviriarlacl ocmompopuonudnsd2s -2u-nudnedceycly-4l--4q-uqiunionloonloen(e1 )(,1s)o, rsboircbiilclailcltaocntoenAe
(A2) (,2s)t,a scthaycbhoytbrointrDin (D3) ,(3c)h, acrhtaarrtuatriunetinBe( 4B) ,(4a)n, dantrdu tnrcuantceaotleMol (M5) .(5).

Sponge-associatedmicrobeshavealsobeenfoundtoproduceanti-influenzacompounds(Table1).

Zhaoetal.[29]elucidated14newisoprenylatedcyclohexanolscoinedastruncateolsA-Nfromthe
sponge-associatedfungusTruncatellaangustata,andthesecompoundsweretestedinvitroagainstthe
influenzaA(H1N1)virus. TruncateolsC,EandMdisplayedbioactivityagainstH1N1,withtruncateol
M (5) being the most potent inhibitor, as shown by its IC value of 2.91 µg/mL. This inhibitory
50
concentrationwasalmostsixfoldlowerthanthatofthepositivecontroloseltamivirat14.52µg/mL.

Truncateol M was predicted to be active at the late stage of the virus infection, likely during the
assemblyorreleasestepofthevirion[29]duetoresemblanceoftheinhibitionpatternsobservedfor
neuraminidase-inhibitordrugs,e.g.,zanamivirandoseltamivir[30]. Inaddition,thepresenceofa
chlorineatominthechemicalstructureoftrucanteolMisofparticularinterestsincehalogenation
oftenenhancesbioactivityofagivencompound[31,32].
Mar.Drugs2016,14, 87 4of66
Table1.Bioactivecompoundswithantiviralactivityfromsponge-associatedmicrobes.
Sponge Origin(Depth) Microorganism Phylum Compound Property Target Reference
Homophymiasp. Touho,NewCaledonia(ND) Pseudomonassp.1531-E7 Proteobacteria 2-undecyl-4-quinolone IC50(10´3µg/mL) HIV-1 [25]
Reducingproteinexpressionand
BightofFetovaia,
Irciniafasciculata Penicilliumchrysogenum Ascomycota SorbicillactoneA activityofreverse HIV-1 [26]
Italy(17.5m)
transcriptase(0.3–1µg/mL)
Stachybotryschartarum
Xestospongiatestudinaria ParacelIslands(ND) MXH-X73 Ascomycota StachybotrinD EC50(3.71µg/mL) HIV-1 [27]
Non-nucleosidereverse
Stachybotryschartarum transcriptaseinhibitor
Xestospongiatestudinaria ParacelIslands(ND) MXH-X73 Ascomycota StachybotrinD EC50(3.09µg/mL) (NNRTI)resistant [27]
HIV-1strain1RT-K103N
Stachybotryschartarum NNRTIresistant
Xestospongiatestudinaria ParacelIslands(ND) MXH-X73 Ascomycota StachybotrinD EC50(10.51µg/mL) HIV-1RT-L100I,K103N [27]
Stachybotryschartarum NNRTIresistant
Xestospongiatestudinaria ParacelIslands(ND) MXH-X73 Ascomycota StachybotrinD EC50(5.87µg/mL) HIV-1RT-K103N,V108I [27]
Stachybotryschartarum NNRTIresistant
Xestospongiatestudinaria ParacelIslands(ND) MXH-X73 Ascomycota StachybotrinD EC50(6.27µg/mL) HIV-1RT-K103N,G190A [27]
Stachybotryschartarum NNRTIresistant
Xestospongiatestudinaria ParacelIslands(ND) MXH-X73 Ascomycota StachybotrinD EC50(2.73µg/mL) HIV-1RT-K103N,P225H [27]
Niphatessp. BeibuwanBay,China(10m) Stachybotryschartarum Ascomycota ChartarutineB IC50(1.81µg/mL) HIV-1 [28]
Niphatessp. BeibuwanBay,China(10m) Stachybotryschartarum Ascomycota ChartarutineG IC50(2.05µg/mL) HIV-1 [28]
Niphatessp. BeibuwanBay,China(10m) Stachybotryschartarum Ascomycota ChartarutineH IC50(2.05µg/mL) HIV-1 [28]
Amphimedonsp. Yongxinisland,China(10m) Truncatellaangustata Ascomycota TruncateolM IC50(2.91µg/mL) H1N1 [29]
PyronepolyeneC-glucoside
Callyspongiasp. Sanya,China(ND) Epicoccumsp.JJY40 Ascomycota iso-D8646-2-6 IC50(56.06µg/mL) H1N1 [33]
PyronepolyeneC-glucoside,
Callyspongiasp. Sanya,China(ND) Epicoccumsp.JJY40 Ascomycota 8646-2-6 IC50(62.07µg/mL) H1N1 [33]
Percentageofinhibition
Unidentified NaozhouSea,China(ND) AspergillusterreusMXH-23 Ascomycota ButyrolactoneIII H1N1 [34]
(53.9%˘0.53%at50µg/L)
5-[(3,4-dihydro-2,2-
dimethyl-2H-1-benzopyran- Percentageofinhibition
Unidentified NaozhouSea,China(ND) AspergillusterreusMXH-23 Ascomycota H1N1 [34]
6-yl)-methyl]-3-hydroxy-4-(4- (57.8%˘1.99%at50µg/L)
hydroxyphenyl)-2(5H)-furanone
(Z)-5-(Hydroxymethyl)-
Unidentified ParacelIslands(ND) AspergillussydowiiZSDS1-F6 Ascomycota 2-(60)-methylhept-20-en- IC50(14.30µg/mL) H3N2 [35]
20-yl)-phenol
Unidentified ParacelIslands(ND) AspergillussydowiiZSDS1-F6 Ascomycota Diorcinol IC50(15.31µg/mL) H3N2 [35]
Mar.Drugs2016,14, 87 5of66
Table1.Cont.
Unidentified Paracelslands(ND) AspergillussydowiiZSDS1-F6 Ascomycota CordyolC IC50(19.33µg/mL) H3N2 [35]
Stachybotryssp.HH1
Unidentified ParacelIslands(ND) ZSDS1F1-2 Ascomycota StachybogrisephenoneB IC50(10.2µg/mL) Enterovirus71(EV71) [36]
Stachybotryssp.HH1
Unidentified ParacelIslands(ND) ZSDS1F1-2 Ascomycota GrisephenoneA IC50(16.94µg/mL Enterovirus71(EV71) [36]
Stachybotryssp.HH1
Unidentified ParacelIslands(ND) ZSDS1F1-2 Ascomycota 3,6,8-Trihydroxy-1-methylxanthone IC50(10.4µg/mL) Enterovirus71(EV71) [36]
Petromicacitrina SacodoPoço,Brazil(5–15m) Bacillussp.B555 Firmicutes Unidentified IC50(27.35µg/mL) Bovineviraldiarrhea [37]
EC50(>500µg/mL) virus
Petromicacitrina SacodoPoço,Brazil(5–15m) Bacillussp.B584 Firmcutes Unidentified IC50(10.24µg/mL) Bovineviraldiarrhea [37]
EC50(277µg/mL) virus
Petromicacitrina SacodoPoço,Brazil(5–15m) Bacillussp.B616 Firmicutes Unidentified IC50(47µg/mL) Bovineviraldiarrhea [37]
EC50(1500µg/mL) virus
Table1isorganisedaccordingtothetargetvirusses.IC50:halfmaximuminhibitoryconcentration;EC50:theconcentrationofadrugthatgivethehalf-maximalresponse;ND:not
determined;HIV:humanimmunodeficiencyvirus;H1N1andH3N2areinfluenzaAvirussubtypes.
Mar.Drugs2016,14, 87 6of66
3. AntibacterialCompounds
The screening procedure for antibacterial activity often includes both Gram positive and
Gram negative target strains, including, e.g., Staphylococcus spp., Streptococcus spp., Bacillus spp.,
Clostridiumspp.,Escherichiaspp.,andPseudomonasspp. Fromamedicalpointofview,thesegenera
receiveattentionbecausetheyarewellrepresentedamongthecausativeagentsforhumaninfectious
diseases,suchaspneumonia,urinarytractandbloodstreaminfections[38,39]. Microbialisolatesfrom
marinespongeshavebeenshowntoexhibitbioactivityagainstawidespectrumofpathogenicbacteria
(Table2). ThenovelthiopeptideantibioticsYM-266183(6)andYM-266184(7)(Figure2),whichwere
isolatedfromthesponge-associatedbacteriumBacilluscereusQN03323,showedantibacterialactivity
againstnosocomialinfectiousGrampositivebacteriainvitro[40,41]. BothYM-266183andYM-266184
effectivelyinhibitedStaphylococcusaureusandvancomycin-resistantEnterococcusfaeciumasindicated
byminimalinhibitionconcentration(MIC)valuesaslowas0.025µg/mL.Inaddition, compound
YM-266184wasfoundparticularlyactiveagainstmethicillinresistantStaphylococcusaureus(MRSA)
withaMICof0.39µg/mL.CompoundYM-266183alsoinhibitedMRSAbutrequiredatwo-foldhigher
concentration of the pure compound. Bioactivity of these thiopeptides was also observed against
StreptococcusepidermidisandEnterococcusspp. (Table2). Thecompoundkocurin(8)wasidentified
from three sponge-associated actinobacteria: Kocuria marina F-276,310, Kocuria palustris F-276,345,
and Micrococcus yunnanensis F-256,446 [42,43]. Kocurin is a new member of the thiazolyl peptide
familyandexhibitedanti-MRSAactivitywithanMICof0.25µg/mL,whichtodateisthemostpotent
anti-MRSAcompoundreportedfromsponge-associatedmicrobes. Scheenemaanetal.[44]isolated
Streptomycessp. HB202fromthespongeHaliclonasimulans,whichleadtodiscoveryofthepolyketide
mayamycin. Invitroassayswithmayamycin(9)showedbioactivityagainstS.aureusandMRSAwith
IC valuesof1.16µg/mLand0.58µg/mLrespectively,alongwithanIC of0.14µg/mLagainst
50 50
Staphylococcusepidermidis[45].
Although many studies on antibacterial activity from sponge-associated microbes included
Gramnegativestrains(Table2),reportsonpronouncedantibacterialcompoundsactiveagainstGram
negativebacteriaarelimitedincomparisontothosethatinhibitGrampositivestrains. Oneofthe
examples of an inhibitor of a Gram negative bacterium is the compound naphthacene glycoside
SF2446A2 (10) isolated from Streptomyces sp. RV15 that was originally obtained from the marine
sponge Dysidea tupha [46]. Naphthacene glycoside SF2446A2 (10) inhibited the Gram-negative
bacteriumChlamydiatrachomatisatanIC valueof2.81˘0.24µg/mL.Reimeretal.[46]underlined
50
that compound 10 not only effectively inhibited the formation of chlamydial inclusion bodies
during the primary infection but also affected the ability of C. trachomatis in producing viable
progeny during the developmental cycle. Chlamydia trachomatis is an obligate intracellular Gram
negative bacterium which is a leading cause of sexually transmitted diseases, and currently
no methods are available to treat this infectious microorganism [46,47]. Li et al. [48] isolated
four new bisabolane-typesesquiterpenoids: aspergiterpenoid A, (´)-sydonol, (´)-sydonic acid,
(´)-5-(hydroxymethyl)-2-(21,61,61-trimethyltetrahydro-2H-pyran-2-yl)phenolandaknowncompound
(Z)-5-(Hydroxymethyl)-2-(61-methylhept-21-en-21-yl)phenolfromasponge-associatedAspergillussp.
(Table2). Ofthesefivesubstances,thecompoundsydonicacid(11)exhibitedthelowestMICvalue
againstEscherichiacoliat1.33µg/mL.ThisisthelowestinhibitionconcentrationagainstE.colireported
fromacompoundproducedbysponge-associatedmicrobesalthoughtheinhibitionconcentrationis
stillhigherthanthepositivecontrolciprofloxacin(0.21µg/mL)(Table2).
Pruksakorn et al. [49] reported three prospective anti-tuberculosis compounds: trichoderin A
(12), A1 and B from the sponge-associated fungus Trichoderma sp. 05FI48. Both under standard
aerobic growth and dormancy-inducing hypoxic conditions, these three compounds inhibited
Mycobacterium smegmatis, M. bovis BCG, and M. tuberculosis H37Rv with MIC values in the range
of0.02–2.0µg/mL.Ofthesethreecompounds,trichoderinAwasthemostpotentcompoundindicated
by the lowest MIC values against those Mycobacterium strains. Additional analysis revealed that
bioactivityoftrichoderinAisbasedonitsabilitytoinhibitadenosinetriphosphate(ATP)synthesis
Mar.Drugs2016,14, 87 7of66
ofmycobacteria[50]. CompoundssuchastrichoderinAareparticularlyimportantbecauseinmany
Mar. Drugs 2016, 14, 87 7 of 79
cases,pathogenssuchasCampylobacterspp.,Helicobacterpylori,andLegionellapneumophilaaredifficult
totreatduetothefactthattheyarepresentinadormantstate[51]. Suchphysiologicallyinactivecells
difficult to treat due to the fact that they are present in a dormant state [51]. Such physiologically
highliynaccotnivteri cbeulltse htioghthlye cnoenetdribfuotrep toro tlhoen ngeueedd foarn ptirboilootnigcutreeda atmntiebniotsti,cw trheiacthmmenatsy, wlehaidcht omtahye leemade trog ence
ofrestihseta enmtesrtgraeninces o[5f 2r,e5s3is]t.ant strains [52,53].

FigurFeig2u.rCeh 2e. mChiceamlisctarlu scttruurcetusroefst ohfe tahne tainbtaicbtaecrtiearliaclo cmompopuounnddssY YMM--226666118833 ((66)),, YYMM--226666118844 (7(7),) k,kocoucruinri n(8),
maya(m8),y mciany(a9m),yncianp (h9t)h, naacpenhtehgaclyencoe sgildyecoSsFid2e4 4SF62A4246(A102) (,1s0y),d soyndiocnaicc iadci(d1 1(1)1a) nadndt rtircichhooddeerriinn AA ((1122)). .
Mar.Drugs2016,14, 87 8of66
Table2.Bioactivecompoundswithantibacterialactivityfromsponge-associatedmicrobes.
Sponge Origin(Depth) Microorganism Phylum Compound Property Target References
Halichondriajaponica Iriomoteisland,Japan(ND) BacilluscereusQNO3323 Firmicutes ThiopeptideYM-266183 MIC(0.025µg/mL) Staphylococcusaureus [40,41]
Halichondriajaponica Iriomoteisland,Japan(ND) BacilluscereusQNO3323 Firmicutes ThiopeptideYM-266184 MIC(0.025µg/mL) S.aureus [40,41]
KielFjord,BalticSea,
Halichondriapanicea Germany(ND) Streptomycessp.HB202 Actinobacteria Mayamycin IC50(1.16µg/mL) S.aureus [45]
Spheciospongiavagabunda RedSea(ND) Micrococcussp.EG45 Actinobacteria MicrolusideA MIC(12.42µg/mL) S.aureusNCTC8325 [54]
Rossisland,Antartica
Isodictyasetifera Pseudomonasaeruginosa Proteobacteria Phenazine-1-carboxylicacid MIC(>4.99µg/mL) S.aureus [55]
(30–40m)
Rossisland,Antartica
Isodictyasetifera Pseudomonasaeruginosa Proteobacteria Phenazine-1-carboxamide MIC(>4.99µg/mL) S.aureus [55]
(30–40m)
Hymeniacidonperleve BohaiSea,China(ND) AspergillusversicolorMF359 Ascomycota 5-Methoxydihydrosterigmatocystin MIC(12.5µg/mL) S.aureus [56]
Laugroup,
Melophussp. Penicilliumsp.FF001 Ascomycota Citrinin MIC(1.95µg/mL) S.aureus [57]
Fijiislands(10m)
Petrosiasp. Jejuisland,Korea(20m) Aspergillusversicolor Ascomycota Averantin MIC(3.13µg/mL) S.aureusSG511 [58]
Petrosiasp. Jejuisland,Korea(20m) Aspergillusversicolor Ascomycota Nidurufin MIC(6.25µg/mL) S.aureusSG511 [58]
Petrosiasp. Jejuisland,Korea(20m) Aspergillusversicolor Ascomycota Averantinandnidurufin MIC(3.13µg/mL) S.aureus285 [58]
Petrosiasp. Jejuisland,Korea(20m) Aspergillusversicolor Ascomycota Averantin MIC(1.56µg/mL) S.aureus503 [58]
Petrosiasp. Jejuisland,Korea(20m) Aspergillusversicolor Ascomycota Nidurufin MIC(3.13µg/mL) Saureus503 [58]
Pseudoalteromonaspiscicida Norharman
Hymeniacidonperleve Nanjiisland,China(ND) Ascomycota MIC(50µg/mL) S.aureus [59]
NJ6-3-1 (beta-carbolinealkaloid)
Halichondriapanicea Bogilisland,Korea(ND) Exophialasp. Ascomycota ChlorohydroaspyronesA MIC(62.5µg/mL) S.aureus [60]
Halichondriapanicea Bogilisland,Korea(ND) Exophialasp. Ascomycota ChlorohydroaspyronesB MIC(62.5µg/mL) S.aureus [60]
SouthChinaSea,
Axinellasp. Eupenicilliumsp. Ascomycota αβ-Dehydrocurvularin MIC(375µg/mL) S.aureus [61]
China(ND)
Pseudomonasfluorescens
CagarrasArchipelago,
Haliclonasp. H40,H41andPseudomonas Proteobacteria Diketopiperazine MIC(512µg/mL) S.aureus [62]
Brazil(4–20m)
aeruginosaH51
SoutheastCoastIndia
Spongiaofficinalis Streptomycessp.MAPS15 Actinobacteria 2-pyrrolidone MIC(500µg/mL) S.aureusPC6 [63]
(10–15m)
2-(21,41-dibromophenyl)-
Dysideaherbacea Koror,RepublicPalau(1m) Oscillatoriaspongeliae Cyanobacteria ND S.aureus [64]
4,6-dibromophenol
Aragusukuisland,
Hyrtiosaltum Vibriosp. Proteobacteria Trisindoline DOI(10mm) S.aureus [65]
Japan(ND)
BidongIsland, SerratiamarcescensIBRL
Xestospongiatestudinaria Proteobacteria Prodigiosin DOI(ď9mm) S.aureus [66]
Malaysia(ND) USM84
Mar.Drugs2016,14, 87 9of66
Table2.Cont.
unidentified SouthChinaSea(10m) Nocardiopsissp.13-33-15 Actinobacteria 1,6-Dihydroxyphenazine DOI(25˘0.6mm) S.aureusSJ51 [67]
and13-12-13
1,6-Dimethoxyphenazine DOI(21˘0.1mm) S.aureusSJ51
Banyuls-sur-Mer,France
Aplysinaaerophoba BacillussubtilisA184 Firmicutes SurfactinIturinFengycin ND S.aureus [68]
(5–15m)
Banyuls-sur-Mer,France
Aplysinaaerophoba BacillussubtilisA190 Firmicutes Surfactin ND S.aureus [68]
(5–15m)
Indole DOI(7–10mm) S.aureus
Halichondriasp. WestCoastofIndia(10m) BacilluslicheniformisSAB1 Firmicutes [69]
3-Phenylpropionic DOI(4–6mm) S.aureus
1,3,8-Trihydroxy-6-
methoxyanthraquinone
BaliBataNationalPark,
Niphatesolemda Curvularialunata Ascomycota (lunatin) DOI(10mm) S.aureus [70]
Indonesia(ND)
BisanthraquinonecytoskyrinA
GurraigSoundKilkieran
Haliclonasimulans BacillussubtilisMMA7 Firmicutes Subtilomycin ND S.aureus [71]
Bay,Ireland(15m)
Polymastiaboletiformis,
GurraigSound,Kilkieran Pseudovibriosp.W64,W69,
Axinelladissimilisand Proteobacteria Tropodithieticacid DOI(ě2mm) S.aureus [72]
Bay,Ireland(15m) W89,W74
Haliclonasimulans
Pseudovibriosp.JIC17,W10,
Polymastiaboletiformis,
GurraigSound,Kilkieran W71,W74,W78,W96,
Axinelladissimilisand Actinobacteria Unidentified DOI(ě1mm) S.aureus [72]
Bay,Ireland(15m) WM33,WC15,WC30,
Haliclonasimulans
HMMA3
Pseudovibriosp.JIC5,JIC6,
W62,W63,W65,W99,
Polymastiaboletiformis,
GurraigSound,Kilkieran WC43,W85,W94,WM31,
Axinelladissimilisand Proteobacteria Unidentified DOI(ě4mm) S.aureus [72]
Bay,Ireland(15m) WM34,WM40,WC13,
Haliclonasimulans
WC21,WC22,WC32,
WC41,HC6,
Vizhinjamcoast,India MIC(68˘2.8µg
Dendrillanigra Streptomycessp.MSI051 Ascomycota Unidentified S.aureus [73]
(10–15m) protein/mL)
Hymeniacidonperleve NanjiIsland,China(ND) Pseudomonassp.NJ6-3-1 Proteobacteria Unidentified DOI(3–5mm) S.aureus [74]
KovalamCoast,
Callyspongiaspp AspergillusflavusGU815344 Proteobacteria Unidentified DOI(27mm) S.aureus [75]
India(5–10m)
CagarrasArchipelago,
Haliclonasp. PseudomonasfluorescensH41 Proteobacteria Unidentified DOI(20mm) S.aureus [76]
Brazil(4–20m)
CagarrasArchipelago,
Haliclonasp. PseudomonasfluorescensH40 Proteobacteria Unidentified DOI(23mm) S.aureus [77]
Brazil(4–20m)
CagarrasArchipelago,
Haliclonasp. PseudomonasfluorescensH41 Firmicutes Unidentified DOI(20mm) S.aureus [77]
Brazil(4–20m)
CagarrasArchipelago,
Haliclonasp. PseudomonasaeruginosaH51 Proteobacteria Unidentified DOI(30mm) S.aureus [77]
Brazil(4–20m)
Mar.Drugs2016,14, 87 10of66
Table2.Cont.
CagarrasArchipelago,
Dragmacidonreticulatus BacilluspumilusDr31 Actinobacteria Unidentified DOI(19mm) S.aureus [77]
Brazil(4–20m)
CagarrasArchipelago,
Petromicacitrina BacilluspumilusPc31 Firmicutes Unidentified DOI(40mm) S.aureus [77]
Brazil(4–20m)
CagarrasArchipelago,
Petromicacitrina BacilluspumilusPc32 Firmicutes Unidentified DOI(40mm) S.aureus [77]
Brazil(4–20m)
CagarrasArchipelago, Pseudovibrioascidiaceicola
Clathrinaaurea Proteobacteria Unidentified DOI(28mm) S.aureus [77]
Brazil(4–20m) Ca31
CagarrasArchipelago, Pseudovibrioascidiaceicola
Paraleucillamagna Proteobacteria Unidentified DOI(27mm) S.aureus [77]
Brazil(4–20m) Pm31
CagarrasArchipelago, Pseudovibriodenitrificans
Mycalemicrosigmatosa Proteobacteria Unidentified DOI(20mm) S.aureus [77]
Brazil(4–20m) Mm37
GurraigSound,Kilkieran
Axinelladissimilis PseudovibrioAd30 Proteobacteria Unidentified ND S.aureus [78]
Bay,Ireland(15m)
Salinisporasp.M102,M403,
HeronIsland,GreatBarrier
Pseudoceratinaclavata M412,M413,M414,SW10, Actinobacteria Unidentified DOI(>5mm) S.aureus [79]
Reef(14m)
SW15andSW17
HeronIsland,
Pseudoceratinaclavata Salinisporasp.SW02 Actinobacteria Unidentified DOI(<5mm) S.aureus [79]
Australia(14m)
Southeastcoastof
Dendrillanigra Streptomycessp.BTL7 Actinobacteria Unidentified DOI(16mm) S.aureus [80]
India(ND)
GuleiPort,Fujian, Bacillussp.HNS004,
Mycalesp. Firmicutes Unidentified DOI(15–30mm) S.aureus [81]
China(ND) HNS010
GuleiPort,Fujian,
Mycalesp. Vibriosp.HNS022,HNS029 Proteobacteria Unidentified DOI(15–30mm) S.aureus [81]
China(ND)
GuleiPort,Fujian,
Mycalesp. Streptomycessp.HNS054 Actinobacteria Unidentified DOI(15–30mm) S.aureus [81]
China(ND)
GuleiPort,Fujian,
Mycalesp. Bacillussp.HNS005 Firmicutes Unidentified DOI(10–15mm) S.aureus [81]
China(ND)
Cobetiasp.HNS027;
Streptomycessp.HNS047,
GuleiPort,Fujian,
Mycalesp. HNS056;Nocardiopsissp. Actinobacteria Unidentified DOI(10–15mm) S.aureus [81]
China(ND)
HNS048,HNS051,HNS055;
Nocardiasp.HNS052
GuleiPort,Fujian,
Mycalesp. Bacillussp.HNS015 Firmicutes Unidentified DOI(8–10mm) S.aureus [81]
China(ND)
GuleiPort,Fujian,
Mycalesp. Pseudomonassp.HNS021 Proteobacteria Unidentified DOI(8–10mm) S.aureus [81]
China(ND)
Cobetiasp.HNS023;Vibrio
sp.HNS038;Labrenziasp.
GuleiPort,Fujian,
Mycalesp. HNS063;Streptomycessp. Actinobacteria Unidentified DOI(8–10mm) S.aureus [81]
China(ND)
HNS049;Nocardiopsissp.
HNS058