**Part 2**

**New Drugs to Face Resistance** 

206 Understanding Tuberculosis – New Approaches to Fighting Against Drug Resistance

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**9** 

*Baltimore, M.D.,* 

*USA* 

**Old and New TB Drugs: Mechanisms** 

Historically, tuberculosis (TB) has been associated with significant morbidity and mortality, and still remains a major global health problem. It is estimated that 2 billion people are latently infected with *Mycobacterium tuberculosis*, resulting in approximately 3 million deaths worldwide per year. Among the unique features of this organism is its ability to establish persistent infection, requiring prolonged antibiotic treatment in order to achieve clinical cure. The basic goals of anti-tuberculosis therapy include rapid killing of actively multiplying bacilli, prevention of acquired drug resistance, and sterilization of infected host tissues to prevent clinical relapse. Official guidelines recommend a minimum of 6 months of combination antibiotic therapy in order to achieve these goals. Clinical isolates in geographic areas with a high prevalence of drug resistance should be tested routinely for susceptibility to first-line anti-tuberculosis agents if resources permit, in order to optimally guide therapy (Karakousis 2009). The emergence of multidrug-resistant TB (MDR-TB), defined as resistance to the first-line drugs isoniazid and rifampicin, and extensively drugresistant TB (XDR-TB), defined as MDR-TB with additional resistance to fluoroquinolones and at least one of the injectable second-line drugs (capreomycin, kanamycin, and amikacin), poses formidable challenges to global TB control efforts. The high global incidence of drug-resistant TB, estimated annually to be ~500,000 cases of MDR-TB of which 5% to 7% represent XDR-TB, underscores the need to understand the molecular mechanisms of drug resistance, with the ultimate goals of developing new techniques for rapid detection

This chapter presents an updated review of the mechanisms of action and resistance of the

**Intrinsic resistance** refers to the innate ability of a bacterium to resist the activity of a particular antimicrobial agent through its inherent structural or functional characteristics. Intrinsic drug resistance in *M. tuberculosis* has been attributed to its unique cell wall properties, including the presence of mycolic acids, which are high-molecular-weight α-alkyl,β-hydroxy fatty acids covalently attached to arabinogalactan, and which constitute a

of drug resistance and identification of new drug targets.

main old and new anti-tuberculosis agents.

**2. Intrinsic and acquired drug resistance** 

**1. Introduction** 

**of Action and Resistance** 

Anastasia S. Kolyva and Petros C. Karakousis *Johns Hopkins University Center for Tuberculosis Research* 
