## 2 Biology and Molecular Basis of Resistance  
_C. trachomatis_ is an obligate intracellular bacterium that occurs in two forms: the elementary body (ET), an infectious form that can survive outside the host cell, and the reticulate body (RT), the replicative form found exclusively within the cell [14]. These two forms differ in size, structure, and type of metabolism, ultimately leading to distinct functions [15]. Transformation from one form to the other is a characteristic of the unique developmental cycle of chlamydia. ETs are 2.5 times smaller than RBs and resistant to osmotic and mechanical challenges, reflecting a specially constructed cell wall reinforced by substantial cross-linking disulfide bonds between and within outer membrane proteins [16; 17; 18]. Within the ET, there is a highly condensed nucleoid as a result of complete shut-down of transcription activities [15]. Upon entering the cell, genes regulating the transcription factors are activated, leading to the conversion of the ET to the RT. The intracellular phase of the chlamdial developmental cycle takes place within a specialized structure called an _inclusion_, which is enclosed by a membrane and provides favorable conditions for the development and division of sensitive RTs [19; 20]. Another important characteristic of the RT is the containment of peptidoglycan within its cell wall [21]--an important building block of many bacteria as well as a pertinent target site for antimicrobial drugs. More precisely, although it was previously believed that _Chlamydia_ does not contain peptidoglycan, recent studies have visualized it in the septum during the binary division of the RT [22] or confirmed its presence by analyzing peptides obtained from lysates of cells infected with _C. trachomatis_[23]. It is well known that under certain stressful conditions, such as tryptophan or iron starvation, exposure to interferon gamma, exposure to penicillin, and even concurrent herpes virus infection, the RB transforms into an enlarged aberrant body (AB) and enters a persistent state [24; 25; 26]. This is a reversible process, and after the stress stimulus is removed, the AB, which does not replicate but is still viable, exits the persistent state and assumes the form and characteristics of a normal RB [24]. Even more intriguing is the discovery that azithromycin, one of the first drugs of choice for chlamydial treatment [27], induces the appearance of aberrant bodies in an in vitro model and entry into a persistent state, which is dependent upon dose and post-infection time [28]. Moreover, in vitro-induced persistent infection by azithromycin was found to be not related to typical mutation for macrolide resistance mutations on _235 rRNA_, _L4_, or _L22_ protein genes, and it was completely recoverable after removal of the drug. Since the reduced susceptibility of clinical isolates of _C. trachomatis_ observed under laboratory conditions is not always result of mutations in specific genes [9], the possibility of multiple resistance mechanisms arises, some of which may be closely linked to the bacterium's ability to enter a persistent state. In any case, the role of the persistent state in the pathogenesis of chronic infection, recurrence, as well as antimicrobial resistance remains to be elucidated. Like other members of the _Chlamydialaceae_ family, and akin to the other obligate intracellular bacteria, _C. trachomatis_ has a reduced genome that is a consequence of genome streamlining during co-evolution within their eukaryotic hosts [29; 30; 31]. It possesses a circularized chromosome of approximately 1.05 Mbp and a highly conserved plasmid of approximately 7.5 kbp in size [31; 32], the latter being the key virulence factor and determinant of pathogenicity of chlamydia species. Plasmid-less strains of _C. trachomatis_ are rare but have been observed, with a consequent reduction in virulence and pathogenicity [33; 34]. Whole-genome sequencing has significantly advanced our understanding of the organization and composition of chlamydia genomes, including _C.