TY - JOUR
T1 - The ADEP biosynthetic gene cluster in Streptomyces hawaiiensis NRRL 15010 reveals an accessory clpP gene as a novel antibiotic resistance factor
AU - Thomy, Dhana
AU - Culp, Elizabeth
AU - Adamek, Martina
AU - Cheng, Eric Y.
AU - Ziemert, Nadine
AU - Wright, Gerard D.
AU - Sass, Peter
AU - Brötz-Oesterhelt, Heike
N1 - Funding Information:
We thank Thomas A. Scott (Zurich, Switzerland) for helpful discussions on experimental work and the manuscript. We are grateful to Günther Muth (Tübingen, Germany), Vladimir Larionov (Bethesda, MD, USA), Till Schäberle (Gießen, Germany), Marc Buttner (Norwich, UK), and Bradley Moore (San Diego, USA) for kindly providing strains and plasmids. We acknowledge financial support by the University of Duesseldorf/Research Centre Juelich (iGRASPseed fellowship to D.T.), the German Center for Infection Research (DZIF 9.704 to N.Z.), the Canadian Institutes of Health Research (FRN-148463 to G.D.W.), the Government of Canada (Vanier award to E.C.), and the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) (SFB766 A17 and TRR261 A01, A02 to H.B.-O., P.S., and D.T.).
Publisher Copyright:
© 2019 American Society for Microbiology.
PY - 2019
Y1 - 2019
N2 - The increasing threat posed by multiresistant bacterial pathogens necessitates the discovery of novel antibacterials with unprecedented modes of action. ADEP1, a natural compound produced by Streptomyces hawaiiensis NRRL 15010, is the prototype for a new class of acyldepsipeptide (ADEP) antibiotics. ADEP antibiotics deregulate the proteolytic core ClpP of the bacterial caseinolytic protease, thereby exhibiting potent antibacterial activity against Gram-positive bacteria, including multiresistant pathogens. ADEP1 and derivatives, here collectively called ADEP, have been previously investigated for their antibiotic potency against different species, structure-activity relationship, and mechanism of action; however, knowledge on the biosynthesis of the natural compound and producer self-resistance have remained elusive. In this study, we identified and analyzed the ADEP biosynthetic gene cluster in S. hawaiiensis NRRL 15010, which comprises two NRPSs, genes necessary for the biosynthesis of (4S,2R)-4-methylproline, and a type II polyketide synthase (PKS) for the assembly of highly reduced polyenes. While no resistance factor could be identified within the gene cluster itself, we discovered an additional clpP homologous gene (named clpPADEP) located further downstream of the biosynthetic genes, separated from the biosynthetic gene cluster by several transposable elements. Heterologous expression of ClpPADEP in three ADEP-sensitive Streptomyces species proved its role in conferring ADEP resistance, thereby revealing a novel type of antibiotic resistance determinant.
AB - The increasing threat posed by multiresistant bacterial pathogens necessitates the discovery of novel antibacterials with unprecedented modes of action. ADEP1, a natural compound produced by Streptomyces hawaiiensis NRRL 15010, is the prototype for a new class of acyldepsipeptide (ADEP) antibiotics. ADEP antibiotics deregulate the proteolytic core ClpP of the bacterial caseinolytic protease, thereby exhibiting potent antibacterial activity against Gram-positive bacteria, including multiresistant pathogens. ADEP1 and derivatives, here collectively called ADEP, have been previously investigated for their antibiotic potency against different species, structure-activity relationship, and mechanism of action; however, knowledge on the biosynthesis of the natural compound and producer self-resistance have remained elusive. In this study, we identified and analyzed the ADEP biosynthetic gene cluster in S. hawaiiensis NRRL 15010, which comprises two NRPSs, genes necessary for the biosynthesis of (4S,2R)-4-methylproline, and a type II polyketide synthase (PKS) for the assembly of highly reduced polyenes. While no resistance factor could be identified within the gene cluster itself, we discovered an additional clpP homologous gene (named clpPADEP) located further downstream of the biosynthetic genes, separated from the biosynthetic gene cluster by several transposable elements. Heterologous expression of ClpPADEP in three ADEP-sensitive Streptomyces species proved its role in conferring ADEP resistance, thereby revealing a novel type of antibiotic resistance determinant.
KW - 4-methylproline
KW - Acyldepsipeptides
KW - Antibiotics
KW - Caseinolytic protease
KW - Natural products
KW - Nonribosomal peptide synthetase
KW - Polyketide synthase
KW - Resistance
KW - Streptomycetes
UR - http://www.scopus.com/inward/record.url?scp=85072848540&partnerID=8YFLogxK
U2 - 10.1128/AEM.01292-19
DO - 10.1128/AEM.01292-19
M3 - Article
C2 - 31399403
AN - SCOPUS:85072848540
SN - 0099-2240
VL - 85
JO - Applied and Environmental Microbiology
JF - Applied and Environmental Microbiology
IS - 20
M1 - e01292-19
ER -