SMT-738: a novel small-molecule inhibitor of bacterial lipoprotein transport targeting Enterobacteriaceae.

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.

Venous ulcer services in the United Kingdom.

OBJECTIVES: To obtain comprehensive information about venous ulcer services throughout the United Kingdom (UK). DESIGN: Questionnaire based survey. MATERIALS: Questionnaire. METHODS: Letters about venous ulcer services were sent to consultant vascular surgeons in all areas of the UK (total 181). Questionnaires were then directed to the appropriate clinician in each area. RESULTS: Responses were received from 177 (98%) areas. Fifteen (8%) had no dedicated service. Completed questionnaires were returned for 112 (63%) areas. Fifty-six (54%) services were managed by acute hospitals, 29 (28%) by primary care (community) and 19 (18%) jointly. Doctors supervised services in 65 (64%) (vascular surgeons 49, dermatologists 12, both 4) and nurses in 31 (33%). New referrals per week were 1-50 based on audit (33%) or estimates (67%). Sixty-three (58%) services had no database. Written guidelines existed for 76% services (90% nurse-supervised and 64% doctor-supervised services--p<0.02). CONCLUSIONS: Dedicated venous ulcer services have been shown to improve healing rates and quality of life. Although now present in most areas of the UK, their organisation varies considerably and many are not based in the community, near patients homes. This survey provides a benchmark for comparison with venous ulcer services in other countries.