title: TarO-specific inhibitors of wall teichoic acid biosynthesis restore β-lactam efficacy against methicillin-resistant staphylococci.
abstract: The widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current β-lactam antibiotics and created an urgent need for new treatment options. We report an S. aureus phenotypic screening strategy involving chemical suppression of the growth inhibitory consequences of depleting late-stage wall teichoic acid biosynthesis. This enabled us to identify early-stage pathway-specific inhibitors of wall teichoic acid biosynthesis predicted to be chemically synergistic with β-lactams. We demonstrated by genetic and biochemical means that each of the new chemical series discovered, herein named tarocin A and tarocin B, inhibited the first step in wall teichoic acid biosynthesis (TarO). Tarocins do not have intrinsic bioactivity but rather demonstrated potent bactericidal synergy in combination with broad-spectrum β-lactam antibiotics against diverse clinical isolates of methicillin-resistant staphylococci as well as robust efficacy in a murine infection model of MRSA. Tarocins and other inhibitors of wall teichoic acid biosynthesis may provide a rational strategy to develop Gram-positive bactericidal β-lactam combination agents active against methicillin-resistant staphylococci.
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Labroli
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Koseoglu
authors.affiliation: Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Zuck
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Mayhood
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Gill
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Mann
authors.affiliation: Merck Research Laboratories, Boston, MA 02115, USA.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Sher
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Ha
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Yang
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Mihir
authors.initials: M
authors.lastname: Mandal
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Yang
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Lianzhu
authors.initials: L
authors.lastname: Liang
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Tawa
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Reshma
authors.initials: R
authors.lastname: Kuvelkar
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: DeVito
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Wen
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Batchlett
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Balibar
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Liu
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Jianying
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Murgolo
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Garlisi
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Payal R
authors.initials: PR
authors.lastname: Sheth
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Flattery
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA. jing.su2@merck.com christopher_tan@merck.com terry_roemer@merck.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA. jing.su2@merck.com christopher_tan@merck.com terry_roemer@merck.com.
authors.forename: Christopher
authors.initials: C
authors.lastname: Tan
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ 07033, USA. jing.su2@merck.com christopher_tan@merck.com terry_roemer@merck.com.
authors.forename: Terry
authors.initials: T
authors.lastname: Roemer
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D053898:Biosynthetic Pathways / Q000187:drug effects*; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism*; D004009:Dicloxacillin / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010641:Phenotype; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013682:Teichoic Acids / Q000096:biosynthesis*; D016896:Treatment Outcome; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D001426:Bacterial Proteins; D013682:Teichoic Acids; D047090:beta-Lactams; D004009:Dicloxacillin