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Brucellosis remains one of the major zoonotic diseases worldwide. As a causative agent of brucellosis, it has many ways to evade recognition by the immune system, allowing it to replicate and multiply in the host, causing significant harm to both humans and animals. The pathogenic mechanism of Brucella has not been elucidated, making the identification of drug targets from the pathogenic mechanism a challenge. Metalloenzymatic targets and some protein targets unique to Brucella are exploitable in the development of inhibitors against this disease. The development of specific small molecule inhibitors is urgently needed for brucellosis treatment due to the antibiotic resistance of Brucella . This review summarizes the research on small molecule inhibitors of Brucella , which could be instructive for subsequent studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Brucellosis is a debilitating febrile illness caused by an intracellular Brucella. The disease is distributed in humans and animals widely, especially in developing countries. Ten species are included in the genus Brucella nowadays; four species of them are pathogenic to humans, which make brucellosis a zoonosis with more than 500,000 new cases reported annually. For human brucellosis, the most pathogenic species is B. melitensis followed by B. suis, while B. abortus is the mildest type of brucellosis. The infection mechanism of Brucella is complicated and mostly relies on its virulence factors. The therapy of the disease contains vaccination and antibiotic. However, there are some defects in currently available vaccines such as the lower protective level and safety. Thus, safe and efficient vaccines for brucellosis are still awaited. The dual therapy of antibacterial is effective in the treatment of brucellosis if a rapid and exact detection method is found., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The facultative intracellular pathogen and zoonotic agent Brucella sp. possesses two carbonic anhydrases (CAs, EC 4.2.1.1), termed bsCA I and bsCA II (in Brucella suis), belonging to the β-class of these metalloproteins. These zinc enzymes, present in many other pathogenic bacteria, have been considered recently as potential antibacterial targets. The catalytic activity of bsCA II is higher than that of bsCA I (for the conversion of CO(2) to bicarbonate). Both enzymes were inhibited by the well-studied inhibitor acetazolamide, a sulfonamide drug. A library of 41 sulfonamides and one sulfamate, among which 12 clinically tested drugs, was used for inhibition studies with bsCA I and II. These compounds were generally much more potent inhibitors of bsCA I (K(Is) of 17-75 nM) than of bsCAII (K(I)s of 84-923nM). However, certain glycosidic sulfonamide derivatives exhibited the same strong inhibitory activity on both bsCA I and bsCA II (K(Is) of 8.9-20 nM). Furthermore, at least one of these glycosylsulfonamides showed a significant inhibition of B. suis growth after 8-11 days of culture in minimal medium. In conclusion, as β-CAs of Brucella are susceptible to inhibition by a wide range of aromatic and heteroaromatic sulfonamides, they may represent novel targets for the development of clinically useful antibacterial agents.

Brucellosis is a highly contagious bacterial zoonosis that affects millions of people worldwide. Brucella is highly infectious, especially when aerosolized. The infection induces severe protracted diseases, which are both debilitating and incapacitating, hence, Brucella melitensis has been considered a potential biological warfare agent. In the battle against Brucella, it is crucial to know its chemical-structure and biochemistry-metabolic characteristics. It is well known that Brucella, as well as many other intracellular bacterial pathogens, has evolved to survive and even proliferate within monocytes and macrophages cells. Depending on the route of entry (complement, Fc, lectin or fibronectin receptors), the fate of the bacteria will vary; it may even segregate from the endocytic route towards the endoplasmic reticulum. This intracellular "non regular" behaviour of Brucella makes treatment difficult. Most antibiotics, although effective in vitro, do not actively pass through cellular membranes, or, once inside, may not reach the discrete intracellular niche where the bacteria is hidden. Therefore, complete eradication of the microorganisms is difficult to achieve, and the incidence of relapses is rather high. Taking these data into consideration, this review will evaluate the past, current and new trends in the control of brucellosis, paying special attention to the drug delivery systems as potential vectors for targeting these intracellular sites where the organisms are located.