## 2 Co-Administration of Two Different Antimicrobial Polymers
### Nitric Oxide co-Administration Systems  
The NO-based polymers containing other biocidal moieties also represent an alternative for the development of more effective antimicrobial materials to fight drug resistance. Over the last years, antimicrobial therapies based on NO demonstrated a robust strategy to kill the most common infectious pathogens [64; 65]. The outstanding antimicrobial properties of NO are derived from its ability to induce irreversible cellular damages via oxidative stresses to different cellular components (_v.gr._, DNA, proteins) by using reactive byproducts such as dinitrogen trioxide and peroxynitrite. These processes are schematically depicted in Figure 4[66]. In addition, the generation of NO resistant strains is limited with this strategy because, apart from an extremely rapid reduction in microbial populations, its mechanism of action is unspecific. Due to the great potential of NO as an antimicrobial agent, considerable research efforts have been made on the synthesis of NO donor molecules, such as \(S\)-nitroo-\(N\) acetylpencilamine (SNAP), which allow the storage and posterior delivery of NO. Likewise, different strategies have also incorporated this NO donor into polymeric materials [67]. For more than a decade, [PERSON]'s group has focused on investigating NO-based antimicrobial polymers obtaining promising results and, more recently, on exploring approaches for the combined therapies in attempts to increase bactericidal efficacy for a broader microbial spectrum. In this context, interesting contributions dealing with dual systems that integrate NO-releasing compounds with other biocides have been reported aiming at reducing microbial resistance acting synergistically. These systems include antimicrobial dendrimers [68; 69; 70; 71], quaternary ammonium polymers [72], silver derivatives [73; 74] or chitosan [75]. Thus, the combinations of NO releasing compounds with antimicrobial polymers containing different biocidal functionalities are discussed next. Figure 4: Antimicrobial mechanisms of NO and its byproducts. Reproduced with permission from reference [66]. Copyright 2012 RSC. Recently, a multi-defense strategy for the preparation of a novel antimicrobial system has been described, where a NO releasing agent (_vgr._, SNAP) and benzophenone based quaternary ammonium molecules (BPAM) [76] were incorporated onto CarboSil(r) polymer (a poly(silicone-carbonate-urethane) terpolymer used in the fabrication of medical devices). Interestingly, the surfaces containing both agents (SNAP/BPAM) exhibited a significantly enhanced antimicrobial activity against _P. aeruginosa_ and _S. aureus_ as compared to both agents tested individually (Figure 5). It was proposed that a sustained release of NO acts against bacteria adhered on these treated surfaces, lowers their viability and favors the biocidal action of BPAM by contact. [PERSON] et al. [77] incorporated NO donor functional groups into a linear amphiphilic terpolymer formed by biocompatible oligoethylene glycol, hydrophobic ethylhexyl and cationic primary amine segments. A cooperative effect was observed in the biofilm dispersal, planktonic and biofilm killing tests against _P. aeruginosa_. In this specific case, the terpolymer had an analytical performance acting as an antimicrobial agent by promoting bacterial death via a membrane wall disruption, as well as NO carrier. NO-releasing compounds have also been combined with antimicrobial dendrimers, well-defined macromolecules with highly branched structures that emulate natural architectures, in which their size and number of arms can be tailored [78]. Based on this approach, the [PERSON]'s group reported that dendrimers can be useful scaffolds for the development of combined therapies [68; 69; 70; 71]. For example, they demonstrated that the addition of NO donors into PAMAM dendrimers modified with QAS of different alkyl chains considerably improves the biocidal performance as compared to non-NO-releasing dendrimers, which were poorly effective to prevent the biofilms formation of _S.