# Current Promising Strategies against Antibiotic-Resistant Bacterial Infections
## 4 Developing Alternatives to Antibiotics
### Antibody Therapies  
Antibodies can be used to prevent and treat diseases. In contrast to several of the aforementioned available clinical vaccines, only three FDA-approved antibody therapies for bacterial infections exist, two of which treat _B. anthracis_ infection and the other one treats _Clostridium difficile_ infection [142]. All of these antibodies consist of human immunoglobulin G (IgG) and recognize secretory toxins. However, many other antibody therapies targeting components of secretory toxins or cell envelopes of GNBPs and GPBPs have failed in clinical trials [142]. As we mentioned above, protective antigen epitopes are important, and most antigens contain both protective and nonprotective epitopes. Thus, the antibodies uniquely recognizing protective epitopes are more likely to have a therapeutic effect on infections. For instance, in previously _S. aureus_-exposed hosts, antibodies elicited from NEAT2 but not the NEAT1 domain of IsdB provided protection against secondary _S. aureus_ infection [138]. More importantly, out of three monoclonal antibodies (mAbs) recognizing the NEAT2 domain, only one (mAb 1C1) provided protection under the above infection circumstances because it resisted competition by antibodies induced by previous _S. aureus_ exposures. Other factors besides the appropriate paratope, including isotype, antibody titer, half-life, antigen-binding affinity, N-297 glycosylation, downstream effectors (complement C1q, FcyRs), and bacterial evasion strategies, can also impact antibody functions against bacterial infections. A mAb 3F6 recognizing the IgG-binding protein (IBP) nSpA, exerted anti-_S. aureus_ activity only under high N-297 galactosylation or afucosylation conditions [143]. The favorable glycosylation enhances the antibody 3F6-IgG interaction with C1q or FcyR, strengthening their opsonphagocytic killing (OPK) of _S. aureus_. Distinct evasion strategies specific to antibodies have been explored in different bacteria. For instance, _S. aureus_ can inhibit antibody functions by producing SpA and IgG-degrading V8 proteases [144; 145]. SpA captured the Fc region of IgG, keeping it from binding to FcyRs, C1q, and FcRn and resulting in decreased OPK activity and half-life of IgG [146]. Notably, mAb IgG variants with R-QVV and R-DDRVV substitutions in the Fc region could disrupt SpA interference improving therapeutic activity in humanized FcRn mouse models. This study demonstrated the significance of overcoming IgG-specific evasion strategies by modifying the Fc region of IgG. Similar to _S. aureus_, ETEC and _Streptococcus pyogenes_ produce IBPs that bind to the Fc region of antibodies [147; 148; 149; 150]. Furthermore, _S. pyogenes_ and _P. aeruginosa_ secreted IgG-degrading enzymes, which cleaved the hinge region or N-glycosylation of IgG [151; 152]. In samples collected from patients with _S. pyogenes_, IgG-Fc was found to bind on the surface IBPs of _S. pyogenes_, along with the detection of cleavage of N-glycosylation of IgG [153; 152]. In conclusion, future directions of generating antibody therapies against bacterial infections should simultaneously consider their paratopes that bind with protective epitopes and their modification by engineering to overcome IgG-specific evasion strategies. Other antibody engineering options for combating bacterial infections have been reported. DSTA4637S is an antibody-antibiotic conjugate that combines a rifampicin-class antibiotic with an engineered human IgG1 that specifically binds to N-acetyl-glucosamine of WTA [154]. This conjugate is designed to kill intracellular reservoirs of _S. aureus_. When DSTA4637S-opsonized _S. aureus_ is taken up by host cells, phagolysosomal proteases cleave the linker between antibody and antibiotic releasing the antibiotic in sufficient concentrations to kill the bacteria. MEDI13902 is a bispecific antibody against _P. aeruginosa_ PcrV, a protein located at the top of the type III secretory system, and Psl, an extracellular polysaccharide [155].