Chapter 28

Small Molecules Involvedin Transkingdom Communicationbetween Plants and Rhizobacteria

Randy Ortiz Castro and Jose Lopez BucioUniversidad Michoacana de San Nicolas de Hidalgo, Instituto de InvestigacionesQuımico-Biologicas, Mexico

28.1 INTRODUCTION

Intensive agriculture based on an overuse of fertilizers andwater has been critical in the supply of food and grainsfor the increasing human population. Negative impacts ofagricultural practices on soils and water have stimulatedthe commercialization of rhizobacterial inoculants to sus-tain crop growth and yield (Conway and Pretty, 1988;Loneragan, 1997; Berg, 2009).

The use of plant growth-promoting rhizobacteria(PGPR) that impact on plant hormone status may havepositive effects on plant biomass production by modify-ing root architecture to capture existing soil resources,including nutrients such as phosphorus (P), nitrogen(N), and iron (Fe) and enhance water acquisition (Doddet al., 2010; see Chapter 53). At least three well-definedparts can be recognized in the developing plant: (i) theroot, the below-ground part of the plant, which providesanchorage and plays an essential role in interactions withPGPR; (ii) the stem, which supports the leaves, flowers,and fruits; and (iii) the shoot, with important functions inreproduction and photosynthesis. The three-dimensionalorganization of plant organs is known as plant architec-ture and has long been considered a major target for cropimprovement. Notably, the green revolution, which greatlycontributed to grain production in the past decades, wasbased on the modification of plant architecture for selec-tion of crop varieties of agronomic relevance (Peng et al.,

Molecular Microbial Ecology of the Rhizosphere, Volume 1, First Edition. Edited by Frans J. de Bruijn. 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

1999; Reinhardt and Kuhlemeler, 2002; Lopez-Bucioet al., 2005; Ross et al., 2005; Wang and Li, 2008).

Growth and development of plants involve the inte-gration of a myriad of endogenous and environmentalsignals which, together with the intrinsic genetic program,determine plant architecture. Plants have a sophisticatedsystem to integrate information from the environment andto actively respond to biotic and abiotic factors; like-wise, they have developed mechanisms for communica-tion among plants and between plants, and their associatemicroorganisms through transkingdom signaling (see alsoChapter 27).

Virtually every aspect of development of the plant,from embryogenesis to senescence, is subject to regulationmediated by different chemical substances known as phy-tohormones or plant growth regulators. A single hormonemay target a wide range of cellular and morphogeneticprocesses, while simultaneously, multiple hormones mayinfluence the same developmental process (Gray, 2004;Suarez-Lopez, 2005).

Plants produce diverse phytohormones with differ-ent chemical identity including volatiles, such as ethyleneand jasmonic acid (JA), small organic compounds, suchas indole-3-acetic acid (IAA or auxin), cytokinins, gib-berellic acid (GA), abscisic acid (ABA), brassinosteroids(BRs), and lipids (Weyers and Paterson, 2001). In general,these compounds regulate every aspect of plant life andall major developmental transitions including germination,

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Ethylene

Cytokinin

JA

SA

Alkamides

Afinin

N-isobutyl-decanamide

IAA

ABA

Cyclo (L-Pro-L-Phe)

Cyclo (L-Pro-L-Val)

Cyclo (L-Pro-L-Tyr)DKPs

AHLs

C4-HL

3-oxo-C12-HL

P. aeruginosaQS signals

Figure 28.1 Small molecule signals that regulateplant architecture. The six classic phytohormones,auxin (IAA), cytokinin, ethylene, jasmonic acid,salicylic acid, and ABA are shown. Novel plantsignals such as alkamides and bacterially-producedN -acyl-l-homoserine lactones and diketopiperazinesare also illustrated. A single hormone can affectmultiple developmental processes, while multiplesignals may have impact on the same morphogeneticprocess. All together, these regulators orchestrateplant architecture.

vegetative development, flowering, fruit production, andsenescence (Bishopp et al., 2006; Santner et al., 2009)(Fig. 28.1).

Root system architecture (RSA) displays considerableplasticity in its morphology and physiology in responseto abiotic (i.e., nutrient availability, heavy metal stress)or biotic signaling (i.e., plant-to-plant or plant–microbe

interactions) modifying lateral root, root hair, andadventitious root formation (Lopez-Bucio et al., 2002;Lopez-Bucio et al., 2003; Chen et al., 2007; Nibau et al.,2008; Ortiz-Castro et al., 2008a). Classic phytohormones,such as auxins and cytokinins, play important roles inthe regulation of RSA and also affect defense responses,indicating multilevel interactions in the physiology

28.2 Plant–Bacteria Interactions in the Rhizosphere 297

of plants (Reed et al., 1998; Casimiro et al., 2001).Moreover, research conducted in the past 10 years hasidentified the N-acylethanolamines (NAEs), alkamides,and N-acyl-l-homoserine lactones (AHLs; see Chapters70–77) as regulators of plant developmental processesand as mediators of bacterial–plant interactions (Blan-caflor et al., 2003; Chapman, 2004; Lopez-Bucio et al.,2006, 2007a; Morquecho-Contreras and Lopez-Bucio,2007; Campos-Cuevas et al., 2008; Morquecho-Contreraset al., 2010; Mendez-Bravo et al., 2010). The aim of thischapter is to summarize recent findings about the signalsinvolved in the interaction of plants with PGPR, particu-larly auxin and cytokinins, because these hormones playessential roles in growth and developmental processes.We also present and discuss some recent informationon plant perception of bacterial quorum-sensing (QS)signals, which may be relevant toward the identificationof beneficial agricultural traits modulated by PGPR.

28.2 PLANT–BACTERIAINTERACTIONS IN THERHIZOSPHERE

Since the advent of the “green revolution,” crop produc-tivity has been highly dependent on the use of chemicalfertilizers such as N and P. This comes at a heavy price.Besides, the leaching of fertilizers into aquatic systemsaccounts for increasing plant and algal blooms, now aglobal problem. The rising costs of N and P fertilizersdriven by the rising costs of fossil fuels and the need fora long-term agricultural sustainability are making naturalalternatives to chemical fertilizers even more attractive.

Plant roots are surrounded by a portion of soil,which is known as the rhizosphere (Walker et al., 2003;Bais et al., 2006). Plants produce a wide range ofcompounds including sugars, organic acids, and vitamins,which are used as nutrients or signals by bacteria (Badriet al., 2009; see Chapter 22). Plant-beneficial bacteriacommonly proliferate in close proximity to the rootsystem, establishing an intimate relationship with plantswith a profound effect on plant immunity and health.At least in part, these effects can be explained becausebacteria release phytohormones (i.e., IAA, ABA, SA,JA, cytokinins, or gibberellins) or may impact on thehomeostasis of several hormone pathways by affectingbiosynthesis, degradation, and/or signaling throughreceptors and/or transcription factors (Costacurta andVanderleyden, 1995; Tsavkelova et al., 2006; van Loon,2007; Dodd et al., 2010). The growth-promoting potentialof PGPR has been studied in annual crops, such as wheat,soybean, lettuce, beans, maize, and barley (Barazaniand Friedman, 1999; Badri et al., 2009; see Chapter53). Some PGPR may fix atmospheric nitrogen as in

the Rhizobium–legume symbiosis (see Chapters 44, 45),or may confer immunity against foliar pathogens byactivating plant defenses, thereby improving plant growthunder different environments (van Loon et al., 2007).

Promotion of root growth is one of the major mark-ers of PGPR (Glick et al., 1995; Patten and Glick, 2002).Rapid establishment of roots, either by proliferation of lat-eral or adventitious roots or root hairs, is advantageous forplants as it increases the exploratory potential of the rootsystem. Many PGPR synthesize plant hormones, and inthis way they may positively affect root growth (Spaepenet al., 2007; Ortiz-Castro et al., 2008b; Dodd et al., 2010).The production of phytohormones and other compoundsthat influence plant development by PGPR is well docu-mented (van Loon, 2007; Barazani and Friedman, 1999;Gray, 2004). The switch between indeterminate and deter-minate growth in roots and in shoots is frequently regu-lated by endogenous or environmental signals that impacton cell division and/or differentiation programs.

28.2.1 Auxin–Cytokinin Ratio inPlant Developmental ProcessesThe control of plant growth by auxin and cytokininsis a well-known example of hormone interactions thatmodulate developmental transitions, particularly in apicaldominance and in root and shoot morphogenesis. Thebalance between auxin and cytokinin is a key regulatorof in vitro organogenesis. Exposing callus cultures to ahigh auxin-to-cytokinin ratio results in root formation,whereas a low ratio of these hormones promotes shootdevelopment (Howell et al., 2003). Apical dominance isone of the classical developmental events believed to becontrolled by the ratio of auxin to cytokinin. This is sup-ported by phenotypic observations in Arabidopsis mutantsimpaired in different aspects of auxin and/or cytokininsignaling. Several mutants overproducing auxin have beendescribed for Arabidopsis thaliana. The sur1/alf1/rty/hsl3(Boerjan et al., 1995), sur2 (Barlier et al., 2000) and itsstronger allele rnt (Bak et al., 2001), and yucca (Zhaoet al., 2001) mutants display similar developmentalalterations correlated with increased auxin levels. Theseinclude an increased apical dominance, root formation,cell elongation, and the formation of epinastic cotyledonsand leaves. In contrast, the cytokinin-overproducing bus1and the allelic sps mutant exhibit the formation of bushyshoots, retarded onset of vascularization, and upwardcurling leaves (Reintanz et al., 2001; Tantikanjana et al.,2001). Moreover, many experiments have demonstratedthe existence of synergistic, antagonistic, and additiveinteractions between these two plant hormones, suggest-ing complex signal interactions (Nordstrom et al., 2004).Cytokinin and auxin have antagonistic roles in rootdevelopment: auxin promotes the formation of lateral

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and adventitious roots (Dubrovsky et al., 2008), whereascytokinins inhibit root formation interfering with theauxin effect (Laplaze et al., 2007).

In many aspects of plant development, it is reason-able to believe that mechanisms of importance for thehomeostatic control of the auxin–cytokinin ratio shouldbe relatively rapid. The site of synthesis is a critical ques-tion for understanding the cross talk of the two hormonesand how they interact. Although, both, CK and IAA canbe produced in roots and shoots (Ljung et al., 2001; Nord-strom et al., 2004), the production of these major hormonalsignals does not occur randomly but is regulated by thelocation of the synthesizing cells in the plant body andtheir developmental stage, and is influenced by environ-mental conditions and by microorganisms. Young shootorgans are the major sites of IAA production (Ljung et al.,2001; Bhalerao et al., 2002), while root tips are major sitesof CK synthesis (Aloni et al., 2006). From the sites of hor-mone production, the signals move in specific structuralpathways and by different mechanisms to regulate plantdevelopment.

28.2.2 Auxin in Plant Responsesto PGPRDiverse bacterial species produce auxins as part oftheir metabolism, including IAA, indole-3-butyric acid(IBA), or their precursors (Martınez-Morales et al., 2003;Spaepen et al., 2007; see Chapters 27, 29). Auxins arequantitatively the most abundant phytohormones secretedby Azospirillum species, and it is generally agreed thatauxin production is the major factor responsible forthe stimulation of root system development and growthpromotion by this bacterium (Spaepen et al., 2007).Auxin synthesis has been demonstrated in Azospiril-lum brasilense (Dobbelaere et al., 1999), in symbioticN-fixing cyanobacteria (Sergeeva et al., 2002), in theactinomycete Frankia (Wheeler et al., 1984), and inRhizobia (Mathesius, 2008). The exudation of variouscompounds from plants has been shown to stimulateIAA biosynthesis in bacteria, which likely use tryptophanexuded by roots as a precursor of IAA (see Chapter29). Flavonoids, which are produced from legume rootsto stimulate IAA synthesis, have also been reportedto induce IAA synthesis in Rhizobium sp. (Theuniset al., 2004; see Chapter 51). There is evidence thatauxin synthesis by bacteria alters root architecture innon-nodulating plants. For example, auxin synthesisby Erwinia herbicola pathovar gypsophilae stimulatesthe formation of tumors in its plant host Gypsophilapaniculata L. (Clark et al., 1993), while bacteriallyproduced auxin may also explain the stimulation of rootelongation in canola by Pseudomonas putida (Xie et al.,1996).

28.2.3 Role of Cytokininsin Growth Promotion by PGPRCytokinins were discovered in the search for compoundsthat enhanced division of plant cells in culture. Cytokininsare N6-substituted adenine derivatives that contain an iso-prenoid derivative side chain. These hormones influencenumerous aspects of plant development and physiology,including seed germination, de-etiolation chloroplastdifferentiation, apical dominance, flower and fruit devel-opment, leaf senescence, and plant–pathogen interactions(Ferreira and Kieber, 2005). Plants continuously usecytokinins to maintain the pools of totipotent stem cellsin their shoot and root meristems (Howell et al., 2003;Leibfried et al., 2005).

The positive effect of cytokinins on growth atthe whole plant level has been demonstrated by theidentification of genes involved in cytokinin percep-tion and signaling. Three sensor histidine kinases,CRE1/AHK4/WOL, AHK2, and AHK3, have been shownto act as cytokinin receptors (Kakimoto, 2003). Thesereceptors activate the expression of several responseregulators in a cytokinin-dependent manner (Brandstatterand Kieber, 1998; Taniguchi et al., 1998). Further down-stream, cytokinin signaling stimulates the G1/S transitionof the cell cycle, which has been proposed to be mediatedby the transcriptional induction of the CYCD3 gene thatencodes a D-type cyclin (Riou-Khamlichi et al., 1999).The cytokinin receptors play redundant functions in trans-ducing the signal to downstream factors. When grownon soil, none of the single cytokinin receptor mutants ofArabidopsis (cre1-12, ahk2-2, ahk3-3) exhibited signif-icant defective phenotype. However, the ahk2-2 ahk3-3double mutants had smaller leaves and shorter stems thandid the wild-type plants. All single and double mutantsproduced apparently normal flowers that yielded viableseeds. Interestingly, the cre1-12 ahk2-2 ahk3-3 triplemutants showed a dwarf phenotype with reduced rootand shoot growth and smaller meristems. These mutantsalso produced inflorescences with nonfunctional flowers,which failed to produce seeds (Higuchi et al., 2004).These data suggest that cytokinin receptors are importantfor plant viability and normal growth. Cytokinins can beproduced by microorganisms. Their production by PGPRhas been well documented and correlated with increasedgrowth of plants (Nieto and Frankenberger, 1990; Garcıade Salamone et al., 2001; Arkhipova et al., 2005). Untilrecently, little was known on the genetic basis and signaltransduction components that mediate the beneficialeffects of cytokinin-producing PGPR. However, a recentreport has provided important information on the roleplayed by cytokinin receptors in plant growth promotionby Bacillus megaterium rhizobacteria. B. megateriumUMCV1 strain was initially isolated from the rhizosphere

28.3 Quorum-Sensing Signals on Plant Growth and Development 299

Control

B. megaterium

Figure 28.2 Bacillus megaterium promotesArabidopsis growth and development throughcytokinin signaling. (a) Arabidopsis WT(Col-0) seedlings were grown on the surface ofagar plates with 0.2× MS medium orcocultivated with B . megaterium at a distanceof 5 cm from the root tip. (b). Arabidopsistransgenic seedlings expressing thecytokinin-inducible ARR5:uidA reporter weregerminated and grown for 5 days on MS 0.2×.(c and e) or cocultivated with B . megaterium .(d and f) at a distance of 5 cm from theprimary root tip. Notice the increased growthpromotion and enhanced expression of thecytokinin reporter in roots of plantscocultivated with B . megaterium .

of bean (Phaseolus vulgaris L.) plants. Cocultivationwith this bacterium promoted biomass production of A.thaliana and bean plants in vitro and in soil (Lopez-Bucioet al., 2007b). This effect was related to altered RSAin inoculated plants with an inhibition in primary rootgrowth followed by an increase in lateral root formationand root hair length. The effects of bacterial inoculationon plant growth and development were found to beindependent of auxin- and ethylene-signaling as revealedby normal responses of auxin-resistant mutants aux1-7,axr4-1, and eir1, and ethylene-response mutants etr1and ein2, and the failure to activate the expression ofauxin-reporter markers.

The involvement of cytokinin signaling in mediatingplant growth promotion by B. megaterium in plants wasfurther investigated using A. thaliana mutants lacking one,two, or three of the cytokinin receptors, and RPN12, agene involved in cytokinin signaling acting downstreamof the receptors. It was found that growth promotion wasreduced in AHK2-2 single- and double-mutant combina-tions and in RPN12. Furthermore, growth promotion andlateral root induction was completely abolished in thecre1-12 ahk2-2 ahk3-3 triple mutant, indicating the impor-tance of cytokinin perception in the plant’s response to B.megaterium (Ortiz-Castro et al., 2008b) (Fig. 28.2).

Later, it was found that cytokinin signaling is impor-tant for plant perception of alkamides, which comprise anovel class of plant signals related to bacterial QS hor-mones. The alkamides have been reported to affect, both,shoot and root system architecture in plants (Lopez-Bucioet al., 2007a).

The study of the effect of rhizobacterial determinantson plant growth promotion and defense responses byPGPR revealed that root-associated bacterial volatile

organic compounds (VOCs) are responsible, at least inpart, for the induction of, both, plant host resistanceand growth promotion (Ryu et al., 2003; Ryu et al.,2004; see Chapter 63). Bacterial VOCs-mediated plantgrowth promotion was absent in the cytokinin receptorloss-of-function cre1 mutant in Arabidopsis, supportinga critical role of the plant growth hormone cytokinin inplant growth promotion. Moreover, the interplay betweencytokinin and SA has been suggested as a molecularmechanism of plant immunity. Cytokinin signalingthrough AHK2 and AHK3 receptors activates SA signal-ing during interaction with Pseudomonas syringae pv.tomato DC3000 (Pst DC3000), a hemibiotrophic bacterialpathogen (Choi et al., 2010). Application of trans-zeatinor the overproduction of endogenous cytokinins enhancedthe plant immune response, which is compromised inahk2 ahk3 knockout mutants. Cytokinins also activatedtype-B Arabidopsis response regulator (ARR) transcrip-tion factor ARR2, which binds to the promoter of theSA marker genes Pathogenesis related 1 and 2 (PR1and 2). Cytokinins have therefore emerged as strongcandidates in mediating the cross talk between plantgrowth promotion and ISR triggered by bacterial VOCs.

28.3 QUORUM-SENSING SIGNALSON PLANT GROWTH ANDDEVELOPMENT

Many bacterial species use small molecule signalingto communicate with each other and to coordinatetheir growth activities. This cell-to-cell communicationmechanism is known as quorum sensing (QS) andrelies on the production, detection, and response to

300 Chapter 28 Small Molecules Involved in Transkingdom Communication

diffusible signals in a cell density-dependent manner(Fuqua et al., 1994; Fuqua and Greenberg, 2002; seeSection 9). QS processes are important to many bacterialspecies in the regulation of a variety of functions suchas symbiosis, virulence, antibiotic production, biofilmformation, exopolysaccharide synthesis, toxin production,extracellular enzyme production, motility, and plasmidtransfer (Schauder and Bassler, 2001; Marketon et al.,2003; Quinones et al., 2005).

Diverse Gram-negative bacteria produce and useAHLs to regulate QS (Fuqua and Greenberg, 2002).These compounds contain a conserved homoserinelactone (HL) ring and an amide (N)-linked acyl sidechain. The acyl groups of naturally occurring AHLs varyfrom 4 to 18 carbons in length; they can be saturated orunsaturated and with or without a C-3 substituent (Watersand Bassler, 2005). These chemical signals are producedby specific enzymes and they are detected by specificreceptors (Pearson et al., 1994; Vannini et al., 2002).The specific activity of the different compounds can bedetermined by the lactone ring, the amide group, and thefatty acid chain length (Vannini et al., 2002; Fuqua andGreenberg, 2002).

Several reports indicate that AHL production is com-mon among plant-associated Pseudomonas but less fre-quent in free-living soil isolates (Elasri et al., 2001; Khmelet al., 2002; D’Angelo-Picard et al., 2005), thus impli-cating an important role of AHL QS in plant–bacteriainteractions. A recent study showed that AHLs modulateRSA, inhibiting primary root growth and inducing lat-eral root and root hair development (Ortiz-Castro et al.,2008a). Interestingly, the AHLs share structural chemicalsimilarity with NAEs and alkamides from plants, and thisopens the possibility that plants can sense AHLs, NAEs,and alkamides by a common genetic mechanism (Lopez-Bucio et al., 2006).

Bacteria have evolved molecular mechanisms toperceive particular AHLs. The first AHL-type QS signalwas described in Vibrio fischeri (Eberhard et al., 1981), inwhich the enzyme LuxI produces the 3-oxo-C6-HL signalthat interacts with its receptor LuxR and consequentlyinduces the transcriptional expression of the lux genesencoding proteins involved in bioluminescence (Enge-brecht et al., 1983; Swartzman et al., 1990; see Chapter73). Another well-known QS system is that of Pseu-domonas aeruginosa, an opportunistic pathogen of ani-mals and plants. In P. aeruginosa, between 5% and 20%of its genes and proteins are directly or indirectly sub-jected to QS regulation (Bauer et al., 2005). P. aeruginosahas two AHL QS sensor proteins, LasR and RhlR, thatare regulated by 3-oxo-C12-HL and C4-HL, respectively.

Recent information has shown that bacteria can com-municate with plants via AHLs, and this is crucial for theinteraction of PGPR as well as plant pathogens with plant

hosts (Cha et al., 1998; Elasri et al., 2001; Khmel et al.,2002; Gonzalez and Marketon, 2003; D’Angelo-Picardet al., 2005; Pierson and Pierson, 2007; see Chapters 71,73). Certain Rhizobium mutants that fail to produce orsense AHLs were unable to induce nodule formation inlegume plants, suggesting that AHLs might participate insymbiotic interactions (Rosemeyer et al., 1998; Danielset al., 2002; Zheng et al., 2006). Higher plants producecompounds that affect QS-regulated responses in bacteria,which are present in root exudates of pea (Pisum sativum)and Medicago truncatula (Teplitski et al., 2000; Gao et al.,2003). This indicates that secretion of compounds by plantroots, which act as AHL signal mimics, may affect AHL-regulated behaviors in bacteria.

The first report that plants can sense AHLs usedM. truncatula. It was found that AHLs modulated defenseand stress responses, protein processing, responses toplant hormones and cytoskeletal elements, as well asprimary and secondary metabolism (Mathesius et al.,2003). The presence of AHL-producing bacteria in therhizosphere of tomato induced the salicylic acid- andethylene-dependent defense response, which plays animportant role in the activation of systemic resistancein plants and conferred protection against the fungalpathogen Alternaria alternata (Schuhegger et al., 2006).

By using a transcriptomic strategy in A. thaliana,von Rad et al. (2008) documented the changes in geneexpression in the plant in response to N-hexanoyl-DL-homoserine lactone (C6-HL), a QS signal produced by thesoil bacterium Serratia liquefaciens MG1. This AHL mod-ulated the expression of genes involved in auxin biosyn-thesis and response, whereas the levels of cytokinins werereduced indicating that AHLs may increase the auxin-to-cytokinin ratio. Interestingly, unlike most other bacterialsignals, C6-HL influenced only a few defense-related tran-scripts and did not induce plant systemic resistance againstPseudomonas syringae. Evidence was provided that Ara-bidopsis takes up bacterial C6-HL and allows its systemicdistribution throughout the plant (von Rad et al., 2008).

The analysis of RSA in A. thaliana seedlings treatedwith increasing concentrations of AHLs ranging from 4to 14 carbons in length was performed by Ortiz-Castroand associates (2008a). Medium chained (C8-C12) AHLsmodulated primary root growth, lateral root formation, androot hair development, and in particular, N-decanoyl-HL(C10-HL) was the most active compound inducing lateralroot formation and root hair development (Fig. 28.3).

C10-HL caused the differentiation of cells at theprimary root meristem region, which was related toa reduction in the expression of cell division markersCycB1:GUS and pPRZ:GUS. The response of primaryroots to C10-HL was unlikely mediated by auxin signal-ing, because C10-HL did not increase auxin-responsivegene expression and the auxin-related mutants, aux1-7,

28.3 Quorum-Sensing Signals on Plant Growth and Development 301

Dodecanoyl–HL

Decanoyl–HL

3–oxo–hexanoyl–HL

Control 24 48 96 µM

NH

O O

NH

O

NH

O

O

O

O

O

O

O

Figure 28.3 N -Acyl-l-homoserine lactones regulate Arabidopsis root system architecture. Representative photographs of primary roots of9-day-old Arabidopsis seedlings grown in the presence of the indicated compounds.

axr2, and doc1, showed similar growth inhibition toC10-HL as observed in wild-type seedlings. It wasalso found that mutant and overexpressor lines for anArabidopsis fatty acid amide hydrolase gene (AtFAAH)sustained contrasting growth response to C10-HL, thussuggesting that plants possess the enzymatic machineryto metabolize AHLs (Ortiz-Castro et al., 2008a).

Certain fatty acid amides from plants, includingNAEs and alkamides, are strong candidates as AHLsignal mimics. These compounds share chemical simi-larity to AHLs and are also capable of regulating rootand shoot architecture (Ramırez-Chavez et al., 2004;Campos-Cuevas et al., 2008; Morquecho-Contreraset al., 2010). Morquecho-Contreras and associates(2010) isolated an Arabidopsis recessive mutant termeddecanamide-resistant root1 (drr1) after screening amutant population for primary root growth resistanceunder treatment with 30 µM of N-isobutyl-decanamidethat represses growth in wild-typeseedlings. The DRR1locus was required at an early stage of pericycle cellactivation to form lateral root primodia. As the drr1mutants were also resistant to inhibition of primary rootgrowth in a medium containing C10-HL, this study

strongly suggests that plants have evolved a geneticmechanism to perceive NAEs, alkamides, and AHLs, allof which modulate root development (Ortiz-Castro et al.,2008a; Morquecho-Contreras et al., 2010).

Alkamides and NAEs represent an interesting groupof natural products, which may interfere with bacterialQS. For instance, the related N-acyl-cyclopentylamides(N-acyl-CPA) showed strong activity to inhibit QS,N-decanoyl-cyclodipentylamide (C10-CPA) being thestrongest inhibitor of virulence factors, including elastaseand pyocyanin. This compound interferes with the lasand rhl QS systems in P. aeruginosa (Ishida et al., 2007).

Perception of AHLs by plants required theparticipation of Cand2 and Cand7, two candidateG-protein-coupled receptors (GPCRs), regulating rootgrowth by the bacterial AHLs and modulating interac-tions between plants and microbes (Jin et al., 2012). Ina separate study, it was reported that the treatment ofArabidopsis roots with N-3-oxo-hexanoyl-homoserinelactone (3OC6-HL) and N-3-oxo-octanoyl-homoserinelactone (3OC8-HL) resulted in significant root elon-gation. The genetic analysis revealed that the T-DNAinsertional mutants of gcr1, encoding a GPCR GCR1,

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were insensitive to 3OC6-HL or 3OC8-HL in assays ofroot growth. The loss-of-function mutants of the solecanonical Gα subunit GPA1 showed no response to AHLpromotion of root elongation, while Gα gain-of-functionplants overexpressing either the wild type or a consti-tutively active version of Arabidopsis Gα exhibited theexaggerated effect on root elongation caused by AHLs.Furthermore, the expressions of GCR1 and gpa1 weresignificantly upregulated after plants were contacted withboth AHLs, indicating that GCR1 and GPA1 are likelyinvolved in AHL-mediated elongation of Arabidopsisroots (Liu et al., 2012). Taken together, the availableevidence suggests that AHLs regulate morphogeneticprocesses in the root in a dose- and structure-dependentmanner, promoting growth in low concentrations andrepressing growth at high levels. This provides insightinto the mechanism of plant responses to bacterial QSsignals (see Chapter 73).

In plants, the activity of phytohormones is modu-lated through the participation of intracellular secondmessengers including Ca2+, nitric oxide (NO), andhydrogen peroxide (H2O2), which participate in multiplephysiological processes, such as systemic acquiredresistance, the hypersensitive response, leaf senescence,programmed cell death, stomatal closure, root gravit-ropism, cell wall formation, and root development (Grantand Loake, 2000; Neill et al., 2002; Mittler et al., 2004;Schuhegger et al., 2006; Tuteja and Mahajan, 2007; Xuanet al., 2008). A global analysis of gene expression changesin A. thaliana, in response to N-isobutyl-decanamide,revealed the participation of defense-responsive transcrip-tional networks, in particular, genes encoding enzymesfor JA biosynthesis and the JA receptor COI1 in plantresponses to alkamides. Moreover, the participation ofNO and H2O2 as mediators of alkamides and AHLsinducing both developmental changes and conferringresistance to the pathogen Botrytis cinerea was recentlyevidenced (Mendez-Bravo et al., 2010; Mendez-Bravoet al., 2011). In consonance with these results, it wasfound that 3-oxo-C10-HL induces the formation ofadventitious roots in explants of mung bean (Vignaradiata) seedlings via H2O2- and NO-dependent cGMPsignaling (Bai et al., 2012).

Compelling evidence that 3-oxo-C14-HL conferredresistance in Arabidopsis against the biotrophic fungiGolovinomyces orontii and the hemibiotrophic bacterialpathogen Pseudomonas syringae pv tomato DC3000 wasprovided by Schikora et al. (2011). The AHL promotedthe activation of mitogen-activated protein kinasesAtMPK3, an AtMPK6 followed by a higher expressionof the defense-related transcription factors WKRY22and WKRY29 and PATHOGENESIS-RELATED1 gene(Schikora et al., 2011). Changes in the cytosolic Ca2+

concentration in root cells were documented in Arabidop-sis seedlings that were treated with 10 µM C4-HL. Thiswas the first evidence suggesting that C4-HL may act asan elicitor from bacteria to plants through Ca2+ signaling,connecting bacterial QS signaling to developmental pro-cesses (Sung et al., 2011). The ability of plants to detectAHLs produced by rhizobacteria in the rhizosphere andthe similarity of these QS signals to alkamides and NAEsopen the possibility that plants have evolved particularreceptor proteins and signal transduction pathways tocommunicate with rhizobacteria. This will represent anongoing area for research in the plant–bacteria interactionmechanisms.

28.4 CYCLIC DIPEPTIDESMODULATE PLANT–BACTERIAINTERACTIONS

The structural simplicity of bacteria belies their extraor-dinary sophistication in manipulating their environment.Nowhere is their versatility more apparent than in theirability to communicate with higher organisms. In ascreen for QS molecules from Vibrio vulnificus thatcould stimulate AHL-dependent QS reporter strains,Park and associates (2006) identified a cyclic dipeptidecyclo(Phe-Pro) rather than an AHL. Cyclo(Phe-Pro) wasreleased into bacterial cell-free culture medium in adensity-dependent manner, with maximum concentrationspresent as cells enter stationary phase. Addition ofeither purified or chemically synthesized cyclo(Phe-Pro)altered expression of the major virulence factors inseveral Vibrio spp., thus representing a potential QSmolecule that contributes to the pathogenesis of thesebacteria (Park et al., 2006; Klose, 2006). The widespreaddistribution of cyclodipeptides (CDs) and their derivatediketopiperazines (DKPs) indicates that these signalscould be part of a function that is common to manybacterial species (Gondry et al., 2009). However, theDKPs have been reported not only in pathogenic speciesbut also in bacteria typified as beneficial to plants such asPseudomonas putida (Degrassi et al., 2002) or to animalssuch as Lactobacillus sp. (Strom et al., 2002; Li et al.,2011). These exciting findings add further complexity totranskingdom cell-to-cell signaling.

DKPs are synthesized by cyclodipeptide synthases(CDPSs), which constitute a family of peptide-bondforming enzymes that use aminoacyl-tRNAs (aa-tRNAs)as substrates to form various cyclodipeptides. The CDPSfamily includes at least eight identified members foundin various bacterial species (Sauguet et al., 2011; Seguinet al., 2011). The CDPS AlbC from Streptomyces nour-sei uses mainly phenylalanyl-tRNAPhe (Phe-tRNAPhe)and leucyl-tRNALeu (Leu-tRNALeu) as substrates to

28.5 Conclusion 303

synthesize cyclo(l-Phe-l-Leu) (Sauguet et al., 2011).Certain DKPs such as cyclo(His-Gly), cyclo(His-Ala),and cyclo(l-His-l-Phe) show antitumor activity reducingthe viability of HeLa, WHCO3 and MCF-7 cells fromcervical, esophageal, and mammary carcinoma (Kanohet al., 1999; Lucietto et al., 2006). Other compoundsincluding cyclo(l-Phe-l-Pro) and cyclo(l-Ile-l-Pro) thatwere isolated from Propionibacterium strains showedactivity against Aspergillus fumigatus and Rhodotorulamucilaginosa (Lind et al., 2007), whereas the cyclicdipeptide cyclo(l-Arg-d-Pro) was found to inhibit thegrowth of the human pathogen Candida albicans (Hous-ton et al., 2002). Most interesting is the proposed roleof DKPs as QS blockers because cyclo(l-Pro-l-Phe)was capable of inhibiting luminescence in V. fischeri(Campbell et al., 2009). Competition studies showed thatcyclo(l-Pro-l-Tyr) and cyclo(l-Phe-l-Pro) antagonizethe 3-oxo-C6-HL-mediated induction of bioluminescense,suggesting that these DKPs may compete for the samebinding site as AHLs (Holden et al., 1999). On theother hand, the cyclo(l-Leu-l-Pro) signal produced byAchromobacter xylosoxidans inhibits aflatoxin productionby Aspergillus parasiticus, modulating the repressionof transcription of the aflatoxin-related genes. This isthe first report of a cyclodipeptide that affects aflatoxinproduction (Yan et al., 2004).

Even though DKPs seem to play many differentfunctions in bacteria, recent information points to a veryimportant role in ecological processes. Ortiz-Castro et al.(2011) explored one facet of P. aeruginosa/Arabidopsisinterspecies relationships by showing that QS pathwaysin P. aeruginosa regulate the biosynthesis of bacterialDKPs that in turn mimic the activity of the plant growthhormone auxin. When grown nearby, P. aeruginosa couldenhance the growth of A. thaliana seedlings by modulat-ing RSA. This effect was enhanced when the bacterialstrains contained mutations in components of the LasI QSsystem. Profiling bacterial extracts for fractions that couldenhance lateral root growth in Arabidopsis led to theidentification of three DKPs, namely cyclo(l-Pro-l-Val),cyclo(l-Pro-l-Phe), and cyclo(l-Pro-l-Tyr), which weremore abundant in the QS mutant strains. DKPs inducedthe auxin reporters DR5:GUS and BA3:GUS in plantroots, and their growth-promoting activity was dependenton key components of the auxin signaling system. Takentogether, these data outline a molecular mechanism bywhich QS modulates bacterial metabolism to facilitatecommunication with its plant host.

Although other Rhizobacteria such as Bacillus spp.or several environmental strains of Pseudomonas caninduce plant growth by direct or indirect means, thereis limited information about the early signaling eventsthat take place during plant perception of bacteria. Plantsare faced with the challenge of how to recognize and

exclude pathogens that pose a genuine threat, whiletolerating more benign organisms. Importantly, the DKPsidentified in P. aeruginosa clearly show the importanceof the LasI QS system in plant growth promotion by thisbacterium and revealed that DKPs are likely involved inphytostimulation through modulating auxin responses.

The beneficial effects of P. aeruginosa LasI mutantsto Arabidopsis in vitro seem to be contradictory withthe notion of P. aeruginosa as a plant pathogen. It istempting to speculate that overproduction of DKPs isbeneficial to plants not only because they directly activatehormonal responses but also because they decreasingvirulence factors in the bacterium. Evidence supportingthis hypothesis comes from a recent report demonstratingthat the human beneficial bacteria Lactobacillus reuteriproduces the cyclic dipeptides cyclo(l-Tyr-l-Pro) andcyclo(l-Phe-l-Pro), which negatively regulate the expres-sion of toxic shock syndrome toxin-1 of Staphylococcusaureus, a human pathogen, and of cholera toxin andtoxin-regulated pilus production in Vibrio cholerae, thusdecreasing their virulence (Bina and Bina, 2010; Liet al., 2011). All this information contributes to a betterunderstanding of interspecies cell-to-cell communicationbetween Lactobacillus and Staphylococcus, and providesa unique mechanism by which endogenous or PGPRstrains may attenuate virulence factors in bacterialpathogens that associate with eukaryotic hosts.

28.5 CONCLUSION

Bacteria interact extensively with plants and develop intocomplex multicellular populations. The relevance of theseinteractions to plant health and disease is just beginningto be understood and appreciated. Accumulating informa-tion has shown the importance of classic phytohormonessuch as auxins and cytokinins in plant growth promotionby rhizobacteria, particularly in the regulation of RSA.The root system can sense and respond to bacterially pro-duced AHLs and DKPs. Among the reported activities ofDKPs, their auxin-like activity as well as the inhibitoryeffects on virulence factors in plant pathogenic bacteriadeserve further attention. Moreover, many plant speciesare able to produce compounds by roots that structurallymimic AHLs, including alkamides and NAEs, perhaps tomodulate the behaviors of their associate bacteria. Cross-kingdom communication between bacteria and eukary-otic organisms is still a young field. The coming yearsof research should help to establish the generalities andspecific facets of the communication between plants andrhizobacteria by means of small molecule signaling, open-ing new strategies for agricultural management based onbioinoculants or their products.

304 Chapter 28 Small Molecules Involved in Transkingdom Communication

ACKNOWLEDGMENTS

This work was supported by the Consejo Nacional deCiencia y Tecnologıa (Grant 80916), the Consejo dela Investigacion Cientıfica (Grant 2.26), and a MarcosMoshinsky fellowship to Jose Lopez Bucio.

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