Structure-activity relationship of the aminomethylcyclines and the discovery of omadacycline.

A series of novel tetracycline derivatives were synthesized with the goal of creating new antibiotics that would be unaffected by the known tetracycline resistance mechanisms. New C-9-position derivatives of minocycline (the aminomethylcyclines [AMCs]) were tested for in vitro activity against Gram-positive strains containing known tetracycline resistance mechanisms of ribosomal protection (Tet M in Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae) and efflux (Tet K in S. aureus and Tet L in E. faecalis). A number of aminomethylcyclines with potent in vitro activity (MIC range of ≤0.06 to 2.0 µg/ml) were identified. These novel tetracyclines were more active against one or more of the resistant strains than the reference antibiotics tested (MIC range, 16 to 64 µg/ml). The AMC derivatives were active against bacteria resistant to tetracycline by both efflux and ribosomal protection mechanisms. This study identified the AMCs as a novel class of antibiotics evolved from tetracycline that exhibit potent activity in vitro against tetracycline-resistant Gram-positive bacteria, including pathogenic strains of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). One derivative, 9-neopentylaminomethylminocycline (generic name omadacycline), was identified and is currently in human trials for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).

In vitro and in vivo antimalarial efficacies of optimized tetracyclines.

With increasing resistance to existing antimalarials, there is an urgent need to discover new drugs at affordable prices for countries in which malaria is endemic. One approach to the development of new antimalarial drugs is to improve upon existing antimalarial agents, such as the tetracyclines. Tetracyclines exhibit potent, albeit relatively slow, action against malaria parasites, and doxycycline is used for both treatment (with other agents) and prevention of malaria. We synthesized 18 novel 7-position modified tetracycline derivatives and screened them for activity against cultured malaria parasites. Compounds with potent in vitro activity and other favorable drug properties were further tested in a rodent malaria model. Ten compounds inhibited the development of cultured Plasmodium falciparum with a 50% inhibitory concentration (IC50) after 96 h of incubation of <30 nM, demonstrating activity markedly superior to that of doxycycline (IC50 at 96 h of 320 nM). Most compounds showed little mammalian cell cytotoxicity and no evidence of in vitro phototoxicity. In a murine Plasmodium berghei model, 13 compounds demonstrated improved activity relative to that of doxycycline. In summary, 7-position modified tetracyclines offer improved activity against malaria parasites compared to doxycycline. Optimized compounds may allow lower doses for treatment and chemoprophylaxis. If safety margins are adequate, dosing in children, the group at greatest risk for malaria in countries in which it is endemic, may be feasible.

Managing Vibrio cholerae with a local beverage: preparation of an affordable ethanol based hand sanitizer.

Research indicates an increased use of hand sanitizers globally, and in particular developing countries where bacterial epidemics such as cholera are common. While there is evidence of availability, high demand and use of hand sanitizers, the incidence of cholera in developing countries remains unabated. Several reasons have been put forward, and cost of hand sanitizers remains dominant. It is in response to this contradictory situation of availability but limited access, that this study was conducted to present an alternative option of formulating a high quality and cost effective ethanol-based sanitizer from a Ghanaian local beverage (akpeteshie). The concentration of ethanol in akpeteshie was determined using gas chromatography. An Ethanol based hand sanitizer (Sample C) was formulated with akpeteshie and tested against Vibrio cholerae using the microbial time -kill kinetics assay. Commercially available ethanol based Equi-Clean hand sanitizer (62%) (Sample D) was used as the standard. Results show that the akpeteshie contained 73.08% ethanol and formulated product (Sample C) contained 63.70% ethanol. Viscosity and pH of Sample C were; 89 rpm (1.48 cps) and 7.30 respectively whiles that of Sample D were; 80 rpm (1.33 cps) and 7.50 respectively. The formulated product (Sample C) was effective against Vibrio cholerae with a gradual reduction in microbial count upon exposure to the organisms at time intervals of 0, 5, 15, 30, 60 and 120 min.

Structure-activity study of pentamidine analogues as antiprotozoal agents.

Diamidine 1 (pentamidine) and 65 analogues (2-66) have been tested for in vitro antiprotozoal activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Dications 32, 64, and 66 exhibited antitrypanosomal potencies equal or greater than melarsoprol (IC(50) = 4 nM). Nine congeners (2-4, 12, 27, 30, and 64-66) were more active against P. falciparum than artemisinin (IC(50) = 6 nM). Eight compounds (12, 32, 33, 44, 59, 62, 64, and 66) exhibited equal or better antileishmanial activities than 1 (IC(50) = 1.8 microM). Several congeners were more active than 1 in vivo, curing at least 2/4 infected animals in the acute mouse model of trypanosomiasis. The diimidazoline 66 was the most promising compound in the series, showing excellent in vitro activities and high selectivities against T. b. rhodesiense, P. falciparum, and L. donovani combined with high antitrypanosomal efficacy in vivo.