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1.
ACS Infect Dis ; 6(9): 2419-2430, 2020 09 11.
Article in English | MEDLINE | ID: mdl-32786279

ABSTRACT

The clinical effectiveness of the important ß-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-ß-lactamase (MBL) enzymes. To address this resistance issue, multiple ß-lactam/ß-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use. Consequently, there exists an unaddressed yet growing healthcare problem due to the rise in recent years of highly resistant strains which produce New Delhi metallo (NDM)-type metallo-carbapenemases. Previously, we reported the characterization of an advanced MBL inhibitor lead compound, ANT431. Herein, we discuss the completion of a lead optimization campaign culminating in the discovery of the preclinical candidate ANT2681, a potent NDM inhibitor with strong potential for clinical development.


Subject(s)
Enterobacteriaceae , beta-Lactamase Inhibitors , Anti-Bacterial Agents/pharmacology , Meropenem/pharmacology , Monobactams , beta-Lactamase Inhibitors/pharmacology
2.
ACS Infect Dis ; 5(1): 131-140, 2019 01 11.
Article in English | MEDLINE | ID: mdl-30427656

ABSTRACT

The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-ß-lactamase (MBL) and serine-ß-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new ß-lactamase inhibitors to be used in conjunction with carbapenems and other ß-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-ß-lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem.


Subject(s)
Anti-Bacterial Agents/pharmacology , Carbapenem-Resistant Enterobacteriaceae/drug effects , Drug Resistance, Multiple, Bacterial , Enterobacteriaceae Infections/drug therapy , beta-Lactamase Inhibitors/chemistry , Carbapenems/pharmacology , Crystallography, X-Ray , Inhibitory Concentration 50 , Meropenem/pharmacology , Microbial Sensitivity Tests , Picolinic Acids/chemistry , Picolinic Acids/pharmacology , Protein Binding , Structure-Activity Relationship , beta-Lactamase Inhibitors/pharmacology , beta-Lactamases
3.
ACS Chem Biol ; 9(11): 2572-83, 2014 Nov 21.
Article in English | MEDLINE | ID: mdl-25222597

ABSTRACT

Bacterial antimicrobial resistance is an escalating public health threat, yet the current antimicrobial pipeline remains alarmingly depleted, making the development of new antimicrobials an urgent need. Here, we identify a novel, potent, imidazoline antimicrobial compound, SKI-356313, with bactericidal activity against Mycobacterium tuberculosis and Gram-positive cocci, including vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). SKI-356313 is active in murine models of Streptococcus pneumoniae and MRSA infection and is potently bactericidal for both replicating and nonreplicating M. tuberculosis. Using a combination of genetics, whole genome sequencing, and a novel target ID approach using real time imaging of core macromolecular biosynthesis, we show that SKI-356313 inhibits DNA replication and displaces the replisome from the bacterial nucleoid. These results identify a new antimicrobial scaffold with a novel mechanism of action and potential therapeutic utility against nonreplicating M. tuberculosis and antibiotic resistant Gram-positive cocci.


Subject(s)
Anti-Bacterial Agents/pharmacology , DNA Replication/drug effects , Gram-Positive Cocci/drug effects , Imidazolines/pharmacology , Mycobacterium/drug effects , Animals , Anti-Bacterial Agents/chemistry , Gram-Positive Cocci/genetics , Imidazolines/chemistry , Mice , Mutation , Mycobacterium/genetics , Structure-Activity Relationship
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