## 7 Quinolone Inactivation/Modification
### Bacteria  
The ability of different bacteria to degrade or inactivate quinolones by non-canonical mechanisms of resistance has also been observed and may undoubtedly be considered as one of the factors underlying species-specific intrinsic levels of resistance to quinolones. Among the microorganisms with a demonstrated ability to degrade or inactivate quinolones, environmental bacteria, such as _Labrys portucalensis_, members of the genera _Mycobacteria_ or _Microbacterium_, or extremofiles like members of the genus _Thermus_, among others, may be found [163; 164; 165; 166]. Furthermore, the ability of relevant human pathogens to degrade or inactivate quinolones not related to canonical mechanisms of quinolones modification (i.e., AAC(6)ID-cr, CrpP) has also been reported, with descriptions of danofloxacin modifications by _P. aeruginosa_[167]. As with fungi, there are a variety of quinolone-modifying routes. For instance, [PERSON] et al. described four different nonfloxacin modification routes in _Microbacterium_: hydroxylation, oxidative defluorination, desethylation and N-acetylation [165]. In 2013, the same group described that norfloxacin N-acetylation in _Microbacterium_ was related to the action of a glutamine synthetase encoded in the gene _glnA_ (GenBank access: JX901058), confirm  
Figure 4: Proposed network of metabolites generated from ciprofloxacin by the brown rot fungus _Gloophyllum striatum_. (**A**) Oxidative decarboxylation. (**B**) Defluorination. (**C**) Hydroylation at C-8. (**D**) Oxidation of the amino moiety. Trace metabolites, detected only by HPLC–MS are represented at a reduced size. Reproduced from reference [158], with the permission of Elsevier. ing this finding by cloning and expressing this gene in _E. coli_, and observing both the ability of the enzyme cloned in _E. coli_ to modify norfloxacin and its effect on ciprofloxacin susceptibility [168] (Figure 5). Nevertheless, the effect of glutamine synthetase on the final MIC of quinolones may also be influenced by a parallel effect on the production of OmpF related to the expression of _gluA_. Thus, an inverse relationship has been observed between the levels of expression of the _glnA_ and _ompF_ genes in _Salmonella enterica_, with lower levels of OmpF negatively affecting the intake of several quinolones, and thereby contributing to increasing the MIC levels to these agents [169]. SilA is another bacterial enzyme which has demonstrated its in vitro activity against different quinolones. Thus, [PERSON] et al. cloned _E. coli_ and purified SilA from the plant-pathogen _Streptomyces ipomoeae_, showing its ability to degrade ciprofloxacin and norfloxacin [170]. Of note, this enzyme also belongs to the lacases family [170]. Further in silico studies of the SilA protein have proposed that the amino acids His\({}_{102}\), Val\({}_{103}\) and Tyr\({}_{108}\) are key in the modification of quinolones, with the first two being proposed to be involved in oxidative decarboxylation of the COOH radical at position 3, while Tyr\({}_{108}\) is involved in the remotion of an oxygen for the carbonyl radical raised at position 4 [171]. A search in GenBank showed that SilA is present in a long series of microorganisms, with most having a high degree of identity with that of _S. ipomoeae_, including the critical amino acids proposed for anti-quinolone activity. While almost all the abovementioned studies were focused on the biodegradation of quinolones in environmental or solid/liquid waste residues, it should be taken into account that all these quinolone-modifying mechanisms are at risk of mobilization to plasmids or other transferable genetic elements, as has been reported, for instance, with _qepA_, with the original source being proposed to be among _Commandaceae_[75], _qnrB_, which is indigenous of _Citrobacter freundii_[172], or _qxAB_, chromosomally encoded in _Klebsiella pneumoniae_[173]. Figure 5: Effect of _glnA_ on the susceptibility levels to norfloxacin.