42 Current Medicinal Chemistry, 2010, 17, 42-60 0929-8673/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd. Neglected Diseases Caused By Bacterial Infections M. Bechtle 1 , S. Chen 1 and T. Efferth* ,2 1 Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany 2 Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Mainz, Germany Abstract: Bacterial infections represent a major health problem, especially in third world countries. In endemic regions, large populations of people are greatly affected, but the medical care is very limited. In this review, the neglected diseases buruli ulcer and trachoma are elucidated. Buruli ulcer is caused by Mycobacterium ulcerans which produces an outstanding immunosuppressive toxin mycolactone that induces an ulcerative, necrotic skin disease. Until today, only the combination of rifampin/streptomycin is used to treat buruli ulcer. However, this therapy is ineffective and expensive. Here, we report new findings that suggest pharma- ceutical formulations such as rifapentine, in combination with clarithromycin or moxifloxacin that have shown promising results in mice footpad trials. Moreover, alternative treatment options such as heat therapy, nitric oxide cremes and French clay show bactericidal effects. The genotyping of M. ulcerans also promises new ways of finding drug targets and vac- cines. Trachoma, induced by the bacterium Chlamydia trachomatis, is the primary infectious cause of blindness worldwide. Re- current infections lead to chronic inflammation of the upper tarsal conjunctiva. As a consequence, scarring and distortion of the eye lids occur, eventually resulting in blindness. First-line medications for trachoma treatment are bacteriostatic agents such as topically applied tetracylines and systematically administered azithromycin. Surgery, environmental im- provements and personal hygiene are further crucial factors in controlling trachoma. Moreover, efforts are being under- taken towards the development of vaccine systems, with the major outer membrane protein and the polymorphic mem- brane protein acting as attractive candidates. Keywords: Azithromycin, buruli ulcer, Chlamydia trachomatis, Mycobacterium ulcerans, phase change material, rifapentine, trachoma, tetracycline. BACTERIAL INFECTIONS The World Health Organization (WHO) claims 14 dis- eases as neglected tropical diseases (NTD), since they occur mostly in tropical and developing areas in Africa, South- America and China [1]. In these countries NTDs are a bur- den, since the disease in combination with the lack of social welfare systems and medical care often lead to a vicious cir- cle for infected patients where they lose their employment and thus the ability to pay for treatment [2]. The fact that merely less than 1% of new developed drugs between 1975 and 1999 were established for NTDs demonstrates that they are greatly disregarded [3]. NTDs arise as a result of the lack of drugs and therapy forms. This in turn is reflected by the number of suffering patients which for instance mounts up to 84 million people for active trachoma, the most prevalent bacterial infection [4]. Therefore, the primary aim of the WHO is to eliminate these diseases by improving medical care for NTDs [1]. Five of these NTDs are caused by bacte- rial infections, namely buruli ulcer (BU), cholera/epidemic diarrhoea diseases, endemic treponematoses (yaws, pinta and endemic syphilis), leprosy and trachoma [1]. Mostly, chil- dren are more susceptible to such infections due to their in- completely developed immune system, except for cholera which affects children and adults in the same way [4]. In the current review, we especially focus on buruli ulcer and trachoma. We selected these diseases as examples for a very well and long known disease trachoma (1500 BC) [5] and a more recently discovered disease BU (1948) [6]. Both *Address correspondence to this author at the Department of Pharmaceuti- cal Biology and Biochemistry, Institute of Pharmacy, University of Mainz, Staudinger Weg 5, 55099 Mainz, Germany; Tel: +49-6131-3924322; Fax: +49-6131-3923752; E-mail: efferth@uni-mainz.de were claimed as neglected diseases by the WHO and treat- ment guidelines were already proposed. However, treatment guidelines for BU established in 2004 are not applicable for pregnant women and bear the possible risk of blood borne transmission of viral infections [7]. In contrast, the commu- nity-targeted SAFE program (S urgery, A ntibiotics, F acial Cleanliness, E nvironmental Improvements) introduced by the WHO in 1996 has shown satisfying results in endemic regions where it has been properly implemented [8]. Yet, some of the application forms of drugs against BU (injec- tion) and trachoma (ointment onto the inner surface of the lower eyelids) require trained staff that has to be allocated to the affected areas which may comprise difficulties in devel- oping countries. Furthermore, treatment in both cases is not accessible for everyone which reinforces the problems of NTDs. Interestingly, these two diseases are triggered by two dif- ferent bacteria strains (trachoma gram-negative-like and bu- ruli ulcer a mycobacteria) that show interesting similarities: both have intracellular stages that complicate the develop- ment of an effective immune response and effective drug applications. We discuss former treatment strategies and possible drug developments for both diseases. In general, it is important in the case of bacterial infections, to develop new antibiotics and vaccines that overcome multi-drug resistance and ensure safer healing properties. BURULI ULCER History and Epidemiology Skin ulcers have been first identified and described in 1897 in Uganda by Albert Cook [9]. Fifty one years later, a