# Current Promising Strategies against Antibiotic-Resistant Bacterial Infections
## 3 Improved Efficacy of Existing Antibiotics
### Antibiotic Delivery Systems  
The recent development of nanomedicine has enabled the design of new drug delivery systems with an improved therapeutic index for the loaded compounds [71]. In addition, some nanomaterials have direct antibacterial activity, which will be discussed later in the section \"Developing alternatives to antibiotics\". Nanoparticle carriers can directly deliver antibiotics to the intracellular environment, where drugs are unable to reach therapeutic levels, and can markedly solve the problem of adverse side effects or toxicity caused by high systemic doses and frequent administrations [72]. Synthesized polymer nanoparticles consisting of covalently attached \(\beta\)-lactams were more effective against MRSA compared to drug-sensitive _S. aureus_[73;74]. Furthermore, these nanoparticles had relatively low toxicity and a pronounced anti-MRSA activity whether administrated systemically or topically [75]. Liposomes are lipid-based nano-delivery systems and have been introduced as drug carriers in the 1970s. Recent major breakthroughs in liposome technology have invigorated the interest in using them as efficient antibiotic delivery systems against ARB [76;77]. An antibiotic-liposome drug, Arikayce, was approved by the FDA in 2018 to treat lung disease caused by a group of bacteria belonging to the _M. avium_ complex [78]. Because of the similarities between the liposome structure and the bacterial membrane composition, liposomes can stimulate fusion with the bacterial membrane and deliver a high dose of antibiotics inside bacteria (Figure 3). The liposome-bacterial fusion technology is a novel promising approach to overcoming non-enzymatic antibiotic resistance of clinical _P. aeruginosa_ strains [79;80], as their resistance mechanisms are  
Figure 3: The ways to improve efficacy of current antibiotics. largely associated with low and non-specific permeability of their outer membrane or the presence of efflux pumps or both [81]. Furthermore, the antibiotic resistance associated with enzymatic hydrolysis can be conquered by liposome-encapsulated antibiotics. Liposomes prepared with phosphatidylcholine and cholesterol-protected piperacillin against \(\beta\)-lactamase-induced hydrolysis in _Staphylococcus_ sp. [82]. _M. tuberculosis_ is capable of infecting and persisting in macrophages. Given that liposomes have an inherent advantage to be internalized by macrophages, rifabutin-entrapped liposomes have been produced to treat chronic infections caused by intracellular _M. tuberculosis_[83]. Biomimetic nano-delivery systems offer a relatively new approach that uses membranes of natural cells to load compounds of interest. Among them, outer membrane vesicles (OMVs) derived from gram-negative bacteria have frequently been used as antibiotic carriers and exhibited a strong potential for antibacterial applications. For instance, _A. buumannni_ OMVs loaded with fluoroquinolone antibiotics specifically invaded gram-negative bacterial cells of multidrug-resistant _P. aeruginosa_, _K. pneumoniae_, and enterotoxigenic _E. coli_ (ETEC) strains and killed them both in vitro and in vivo [84]. Another study used _E. coli_-derived OMVs to encapsulate rifampicin [85], an antibiotic that is typically used for the treatment of _S. aureus_ and _M. tuberculosis_ infection but not for gram-negative bacteria due to their double-membrane structure. The group reported that rifampicin-loaded OMVs greatly increased the intracellular concentration of rifampicin in _E. coli_, but not in _S. aureus_. When administered to mice, those OMVs elevated the survival rate of infected specimens and reduced the bacterial load in tissues. Additionally, aptamers, small single-stranded oligonucleotides (DNA or RNA) that bind to their specific targets with high affinity and selectivity, can be designed for the delivery of antibiotics. Using a whole bacterium-based procedure of systematic evolution of ligands by exponential enrichment (SELEX), a panel of aptamers specifically binding to _S.