## 6 Acquired Drug-Resistance of Mtb  
A cocktail of different drugs is used to treat TB. Each molecule binds to one or more target, thus inhibiting their functions. The continuous drug exposure during lengthy treatments and the noncompliance of patients to drug regimens, pushes Mtb to select for mutations in genes encoding drug targets, responsible for development of the majority of resistances in clinical strains [20]. A list of the major target genes that, in the case of mutation, confer resistance to the drugs of the WHO groups A, B and C, is shown in Table 1[97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125]. Many excellent reviews report the genetic mechanisms involved in this resistance to RIF, INH, KM, CP and other drugs [18; 126; 23; 24; 98; 118; 23]. \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Group** & **Drug** & **Target Gene/s** & **Gene Product (Function Affected)** & **References** \\ \hline A & LFX or MFX & \(gyrA\) & \begin{tabular}{c} DNA gyrase, subunit A (DNA \\ replication) \\ \end{tabular} & [97; 98] \\ \hline  & & \(gyrB\) & \begin{tabular}{c} DNA gyrase, subunit B (DNA \\ replication) \\ \end{tabular} & [98; 99] \\ \hline  & BDQ & \(atpE\) & \begin{tabular}{c} ATP synthase, subunit F0 (ATP \\ synthesis) \\ \end{tabular} & [100; 101] \\ \hline  & & \(rc0678\) & Transcriptional regulator (drug efflux) & [100; 101] \\ \hline  & LNZ & \(rplC\) & \begin{tabular}{c} 50S ribosomal protein L3 (protein \\ synthesis) \\ \end{tabular} & [100; 102] \\ \hline  & & \(rrl\) & 23S RNA (protein synthesis) & [100; 102] \\ \hline B & CFZ & \(r0678\) & Transcriptional regulator (drug efflux) & [100; 103] \\ \hline  & & \(r1979c\) & \begin{tabular}{c} (Possible permease involved in \\ aminoacid transport) \\ \end{tabular} & [100; 103] \\ \hline  & & \(r2535c\) & \begin{tabular}{c} (PepQ putative aminopeptidase) \\ \end{tabular} & [103; 104] \\ \hline  & CS or TRD & \(alr\) & \begin{tabular}{c} Alanine racemase (peptidoglycan \\ synthesis) \\ \end{tabular} & [105] \\ \hline C & EMB & \(embCAB\) & \begin{tabular}{c} Arabinfouranoyltransferases \\ (arabinogalactan synthesis) \\ \end{tabular} & [106; 107] \\ \hline  & & \(ubiA\) & \begin{tabular}{c} Phosphoribosyltransferase(cell wall \\ synthesis) \\ \end{tabular} & [108; 109] \\ \hline  & DLM & \(ddn\) & \begin{tabular}{c} Deazaflavin (F\({}_{420}\))-dependent \\ nitrooreductase (mycolic acid \\ synthesis) \\ \end{tabular} & [110] \\ \hline  & & \(fgd\)-1 & \
\begin{tabular}{c} Glucose-6-phosphate dehydrogenase \\ (F\({}_{420}\) synthesis) \\ \end{tabular} & [110] \\ \hline  & & \(fbiA\) & Protein FbiA (F\({}_{420}\) synthesis) & [110] \\ \hline  & & \(fbiB\) & Protein FbiB (F\({}_{420}\) synthesis) & [110] \\ \hline  & & \(fbiC\) & Protein FbiC (F\({}_{420}\) synthesis) & [110] \\ \hline  & & & \\ PZA &
\begin{tabular}{c} Pyrazinamidase (conversion of PZA \\ into pyrazinoic acid, resulting in \\ dysfunctions of membrane potential) \\ \end{tabular} & [98; 111] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Drugs of the World Health Organization (WHO) groups A, B and C, and list of the most common drug resistance-related target genes. Phenotypic testing is still considered a gold standard for Mtb DST, which is accurate, but takes at least two weeks for results [98]. However, a pivotal role has been recently played by the more and more rapid molecular methods to diagnose drug-resistant TB by the identification of chromosomal mutations, including line probe assays, the Xpert MTB/RIF system (Cepheid, Sunnyvale, CA, USA), target gene sequencing, whole genome sequencing (WGS), point-of-care nucleic acid amplification devices [9, 127, 128]. The Treatment Action Group (TAG) recently released the pipeline report 2019 on TB diagnostics [129]. The TAG-stratified DST tests for decentralized and centralized laboratories.