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.

Effects of i.v. anaesthetic agents on the chemotaxis of eosinophils in vitro.

Polymorphonuclear eosinophilic leucocytes (PME) participate in wound healing processes, the inflammatory response, bronchial asthma, allergies and defence against invading parasites. We have examined the effects of thiopental, methohexital, propofol, etomidate and ketamine on PME chemotaxis in vitro. PME were isolated from venous blood samples of 10 healthy volunteers using multi-stage Percoll gradient centrifugation. Eosinophilic chemotaxis was determined using a 48-well microchemotaxis chamber. Thiopental 150 micrograms ml-1 and etomidate 0.32 microgram ml-1 caused significant (P < or = 0.05) inhibition of PME chemotaxis. We conclude that thiopental and etomidate may have an adverse influence on wound healing processes and parasitic diseases. Further studies are recommended.

Haemophilia in Somalia.

As first step for the development of a programme of haemophilia care, the disease was diagnosed locally in 5 bleeders. These patients were all affected by severe haemophilia A. They were treated with fresh frozen plasma for bleedings. All of them were negative for antibodies to HIV. The potentialities of the Blood Transfusion Centre at Mogadishu are such that with little effort it could produce amounts of cryoprecipitate sufficient to treat most of the patients living in the central region of the country where the capital, Mogadishu, is located.

Distribution of blood groups in the East African Somali population.

The results of a population survey on blood group distribution in Somalia, East Africa, are presented. Over 1,000 subjects were tested for most blood groups included in the survey. The sampling covered the whole country and was well in accordance with the population density as estimated by the recorded birth places of the subjects. Altogether, 46 blood group antigens were tested, partly common antigens within 11 of the major blood group systems, but also infrequent and very frequent antigens, some not tested before in Africa, were included. The results were compared with the available data for other related peoples and for populations from the same geographical area. The standard genetic distances were also applied in the comparison. The results suggest that only a minor component in the genetic constitution of the Somali population can be ascribed to Caucasian admixture. They are markedly in contrast with some earlier findings. During the survey we observed a previously unknown Rh gene complex occurring with a polymorphic frequency in Somalis.

Evidence for a 'new' Rh gene complex producing the rare Cx (Rh9) antigen in the Somali population of East Africa.

Four unrelated propositi with an unusual Cx-positive Rh phenotype were found during a population survey of 513 Somalis. The Rh phenotypes of the propositi and their available relatives showed that the gene that produces the Cx antigen differs from that found in whites in that it is inherited with an Rh gene complex that produces no C or D. Instead, this gene complex produced es, c, and probably V, although it appeared that no f (ce) antigen was made. These findings suggest that Cx cannot be considered a simple variant form of C but rather a distinct rare Rh antigen that may occur in association with different Rh gene complexes.