Spectinamides: a new class of semisynthetic antituberculosis agents that overcome native drug efflux.
Although the classical antibiotic spectinomycin is a potent bacterial protein synthesis inhibitor, poor antimycobacterial activity limits its clinical application for treating tuberculosis. Using structure-based design, we generated a new semisynthetic series of spectinomycin analogs with selective ribosomal inhibition and excellent narrow-spectrum antitubercular activity. In multiple murine infection models, these spectinamides were well tolerated, significantly reduced lung mycobacterial burden and increased survival. In vitro studies demonstrated a lack of cross resistance with existing tuberculosis therapeutics, activity against multidrug-resistant (MDR) and extensively drug-resistant tuberculosis and an excellent pharmacological profile. Key to their potent antitubercular properties was their structural modification to evade the Rv1258c efflux pump, which is upregulated in MDR strains and is implicated in macrophage-induced drug tolerance. The antitubercular efficacy of spectinamides demonstrates that synthetic modifications to classical antibiotics can overcome the challenge of intrinsic efflux pump-mediated resistance and expands opportunities for target-based tuberculosis drug discovery.
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Richard E
RE
Lee
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Julian G
JG
Hurdle
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Jiuyu
J
Liu
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
David F
DF
Bruhn
Institut für Medizinische Mikrobiologie, Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland.
Tanja
T
Matt
Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, USA.
Michael S
MS
Scherman
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Pavan K
PK
Vaddady
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Zhong
Z
Zheng
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Jianjun
J
Qi
Institut für Medizinische Mikrobiologie, Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland.
Rashid
R
Akbergenov
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Sourav
S
Das
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Dora B
DB
Madhura
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Chetan
C
Rathi
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Ashit
A
Trivedi
Departamento de Microbiología, Medicina Preventiva y Salud Pública, Universidad de Zaragoza, Zaragoza, and CIBER Enfermedades Respiratorias (CIBERES), Spain.
Cristina
C
Villellas
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Robin B
RB
Lee
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Rakesh
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Samanthi L
SL
Waidyarachchi
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Dianqing
D
Sun
Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, USA.
Michael R
MR
McNeil
Departamento de Microbiología, Medicina Preventiva y Salud Pública, Universidad de Zaragoza, Zaragoza, and CIBER Enfermedades Respiratorias (CIBERES), Spain.
Jose A
JA
Ainsa
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
Helena I
HI
Boshoff
Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, USA.
Mercedes
M
Gonzalez-Juarrero
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Bernd
B
Meibohm
Institut für Medizinische Mikrobiologie, Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland.
Erik C
EC
Böttger
Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, USA.
Anne J
AJ
Lenaerts
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012270:Ribosomes / Q000187:drug effects; D000198:Spectinomycin / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*
D018528:ATP-Binding Cassette Transporters; D000577:Amides; D000995:Antitubercular Agents; D001426:Bacterial Proteins; C519050:Rv1258c protein, Mycobacterium tuberculosis; D000198:Spectinomycin