A new role for penicillin acylases: Degradation of acyl homoserine lactone quorum sensing signals by Kluyvera citrophila penicillin G acylase

Mukherji, Ruchira; Varshney, N.K.; Panigrahi, Priyabrata; Suresh, C.G.; Prabhune, Asmita

doi:10.1016/j.enzmictec.2013.12.010

Cited by 48 publications

(64 citation statements)

References 19 publications

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“…Among all AHL acylases previously identified (12–20), MacQ has the broadest substrate specificity toward various AHLs, ranging from C 6 to C 14 in length (Table 1). Besides, MacQ was also able to inactivate a variety of β-lactams, including penicillin derivatives (penicillin G, ampicillin, amoxicillin, and carbenicillin) and cephalosporin derivatives (cephalexin and cefadroxil) (Table 2), although known β-lactam acylases mainly degrade only penicillin G, ampicillin, and cephalexin (22, 23).…”

Section: Resultsmentioning

confidence: 99%

“…Besides, MacQ was also able to inactivate a variety of β-lactams, including penicillin derivatives (penicillin G, ampicillin, amoxicillin, and carbenicillin) and cephalosporin derivatives (cephalexin and cefadroxil) (Table 2), although known β-lactam acylases mainly degrade only penicillin G, ampicillin, and cephalexin (22, 23). Furthermore, MacQ showed much broader substrate specificity than two AHL acylases (AhlM and Kc PGA) known to degrade penicillin G. It has been reported that AhlM was unable to degrade HSLs with a chain smaller than C 8 and cephalosporin-related β-lactams (19), whereas Kc PGA did not show any degradation activity against HSLs with a chain larger than C 8 (20). Thus, MacQ is a unique bifunctional acylase with broad substrate specificity toward AHLs and β-lactam antibiotics.…”

Section: Resultsmentioning

confidence: 99%

“…So far, it has been reported that only two experimentally characterized AHL acylases (AhlM from Streptomyces sp. strain M664 and Kc PGA from Kluyvera citrophila DMSZ 2660) catalyze penicillin G as just one of the substrates (19, 20), and their in vivo contributions to antibiotic resistance have never been discussed. Furthermore, the phylogenetic diversity of bifunctional acylases remains largely unclear, because the bifunctionality is rarely found.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Quorum-Quenching N -Acylhomoserine Lactone Acylase from Acidovorax sp. Strain MR-S7 Mediates Antibiotic Resistance

Kusada

Tamaki

Kamagata

et al. 2017

Appl Environ Microbiol

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N-Acylhomoserine lactone acylase (AHL acylase) is a well-known enzyme responsible for disrupting cell-cell communication (quorum sensing) in bacteria. Here, we isolated and characterized a novel and unique AHL acylase (designated MacQ) from a multidrug-resistant bacterium, Acidovorax sp. strain MR-S7. The purified MacQ protein heterologously expressed in Escherichia coli degraded a wide variety of AHLs, ranging from C6 to C14 side chains with or without 3-oxo substitutions. We also observed that AHL-mediated virulence factor production in a plant pathogen, Pectobacterium carotovorum, was dramatically attenuated by coculture with MacQ-overexpressing Escherichia coli, whereas E. coli with an empty vector was unable to quench the pathogenicity, which strongly indicates that MacQ can act in vivo as a quorum-quenching enzyme and interfere with the quorum-sensing system in the pathogen. In addition, this enzyme was found to be capable of degrading a wide spectrum of β-lactams (penicillin G, ampicillin, amoxicillin, carbenicillin, cephalexin, and cefadroxil) by deacylation, clearly indicating that MacQ is a bifunctional enzyme that confers both quorum quenching and antibiotic resistance on strain MR-S7. MacQ has relatively low amino acid sequence identity to any of the known acylases (<39%) and has among the broadest substrate range. Our findings provide the possibility that AHL acylase genes can be an alternative source of antibiotic resistance genes posing a threat to human health if they migrate and transfer to pathogenic bacteria.IMPORTANCE N-Acylhomoserine lactones (AHLs) are well-known signal molecules for bacterial cell-cell communication (quorum sensing), and AHL acylase, which is able to degrade AHLs, has been recognized as a major target for quorum-sensing interference (quorum quenching) in pathogens. In this work, we succeeded in isolating a novel AHL acylase (MacQ) from a multidrug-resistant bacterium and demonstrated that the MacQ enzyme could confer multidrug resistance as well as quorum quenching on the host organism. Indeed, the purified MacQ protein was found to be bifunctional and capable of degrading not only various AHL derivatives but also multiple β-lactam antibiotics by deacylation activities. Although quorum quenching and antibiotic resistance have been recognized to be distinct biological functions, our findings clearly link the two functions by discovering the novel bifunctional enzyme and further providing the possibility that a hitherto-overlooked antibiotic resistance mechanism mediated by the quorum-quenching enzyme may exist in natural environments and perhaps in clinical settings.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Novel Quorum-Quenching N -Acylhomoserine Lactone Acylase from Acidovorax sp. Strain MR-S7 Mediates Antibiotic Resistance

Kusada

Tamaki

Kamagata

et al. 2017

Appl Environ Microbiol

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“…In addition, penicillin acylases and their close homologues from http://dx.doi.org/10.1016/j.jsb.2015.12.008 1047-8477/Ó 2015 Elsevier Inc. All rights reserved. different bacteria have been reported to show a varied substrate spectrum, sometimes showing promiscuity towards binding Pen V, bile salt and other substrates (Kumar et al, 2006;Mukherji et al, 2014). We have reported the unique kinetic behavior and specificity of penicillin V acylase from a Gram-negative plant pathogen Pectobacterium atrosepticum (Avinash et al, 2013(Avinash et al, , 2015 and its inhibition by bile salts.…”

Section: Introductionmentioning

confidence: 92%

Structural analysis of a penicillin V acylase from Pectobacterium atrosepticum confirms the importance of two Trp residues for activity and specificity

Avinash

Panigrahi

Chand

et al. 2016

Journal of Structural Biology

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“…The AHL-acylase PA0305 from P. aeruginosa shows a low level of activity on penicillin G and V (Wahjudi et al, 2011). A more recent study (Mukherji et al, 2014) showed that the K. citrophila PGA degrades C6-C8 AHLs, although at a much lesser rate than AHL acylases. Ec PGA did not show any activity towards AHLs, despite having a high sequence homology with the K. citrophila PGA.…”

Section: Acyl Homoserine Lactone (Ahl) Acylases Involved In Signalingmentioning

confidence: 97%

Penicillin acylases revisited: importance beyond their industrial utility

Avinash

Pundle

Ramasamy

et al. 2014

Critical Reviews in Biotechnology

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It is of great importance to study the physiological roles of enzymes in nature; however, in some cases, it is not easily apparent. Penicillin acylases are pharmaceutically important enzymes that cleave the acyl side chains of penicillins, thus paving the way for production of newer semi-synthetic antibiotics. They are classified according to the type of penicillin (G or V) that they preferentially hydrolyze. Penicillin acylases are also used in the resolution of racemic mixtures and peptide synthesis. However, it is rather unfortunate that the focus on the use of penicillin acylases for industrial applications has stolen the spotlight from the study of the importance of these enzymes in natural metabolism. The penicillin acylases, so far characterized from different organisms, show differences in their structural nature and substrate spectrum. These enzymes are also closely related to the bacterial signalling phenomenon, quorum sensing, as detailed in this review. This review details studies on biochemical and structural characteristics of recently discovered penicillin acylases. We also attempt to organize the available insights into the possible in vivo role of penicillin acylases and related enzymes and emphasize the need to refocus research efforts in this direction.

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A new role for penicillin acylases: Degradation of acyl homoserine lactone quorum sensing signals by Kluyvera citrophila penicillin G acylase

Cited by 48 publications

References 19 publications

A Novel Quorum-Quenching N -Acylhomoserine Lactone Acylase from Acidovorax sp. Strain MR-S7 Mediates Antibiotic Resistance

A Novel Quorum-Quenching N -Acylhomoserine Lactone Acylase from Acidovorax sp. Strain MR-S7 Mediates Antibiotic Resistance

Structural analysis of a penicillin V acylase from Pectobacterium atrosepticum confirms the importance of two Trp residues for activity and specificity

Penicillin acylases revisited: importance beyond their industrial utility

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