ABSTRACT
Carbapenem-resistant Enterobacteriaceae (CREs) are described by the Centers for Disease Control as an urgent threat, and there is a critical need for new therapeutic agents able to treat infections caused by these pathogens. Herein, we describe the microbiological profile, the mechanism f action, and the in vitro safety as well as the pharmacokinetic (PK)/PD profile of SMT-738, a small molecule belonging to a new chemical class. SMT-738 is active against Enterobacterales [including multi-drug-resistant Escherichia coli with 90% of isolates having a minimum inhibitory concentration (MIC90) of 1 µg/mL and Klebsiella pneumoniae 2 µg/mL] and inactive against a broad panel of Gram-negative and Gram-positive pathogens. SMT-738 displays rapid bactericidal activity (2-4 h) and has a low propensity for resistance development (less than ~10-9). Characterization of resistant mutants following exposure to SMT-738 identified mutations within the lipoprotein transport complex (LolCDE), a clinically unexploited and essential bacterial molecular target in Gram-negative bacteria. SMT-738 has a promising in vitro toxicology profile. Furthermore, PK studies demonstrated that when dosed intravenously, SMT-738 maintained exposure levels across infection sites (bloodstream/urinary tract/lung). Proof-of-concept studies across multiple murine in vivo infection models (bloodstream/pneumonia/urinary tract) demonstrated that SMT-738 significantly reduced the bacterial burden compared to baseline and vehicle control. SMT-738 represents a promising novel drug candidate being developed to address clinically challenging serious life-threatening infections caused by highly resistant Enterobacteriaceae including CRE.
Subject(s)
Anti-Bacterial Agents , Enterobacteriaceae Infections , Mice , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Enterobacteriaceae/genetics , Gram-Negative Bacteria , Klebsiella pneumoniae/genetics , Lipoproteins , Microbial Sensitivity Tests , Enterobacteriaceae Infections/drug therapyABSTRACT
In this 18 year old female patient with adolescent crisis, psychic regression and cyclic abdominal pain, the diagnosis of an acute intermittent porphyria was made by positive urine finding of porphobilinogen, by low serum measurement of the enzyme urosynthase and the positive genetic mutation of this enzyme. The article gives a brief report of the pathogenesis, clinical findings, diagnostic tests and the current therapies being undertaken. Further, a list of medications which are indicated or contraindicated relating to the patient with acute intermittent porphyria is noted.
