3 Challenges of conventional drugs for the treatment of MRSA infection
3.1 Antibiotics
Antibiotics are used for MRSA infection. Long-term use of antibiotics causes resistance, which is due to the immune evasion strategies of bacteria. The use of antibiotics also impairs phagocytic bactericidal functions and weakens the host’s immunity [3]. Additionally, oral antibiotic treatment can disrupt the normal intestinal flora, affecting lung or other tissue immunity to bacteria[53]. Antibiotic resistance and side effects limit its utilization.
3.2 Optimized antibiotics
Optimized antibiotics, including antibody-antibiotic conjugate (AAC) and antibiotic adjuvants, have been proposed to combat MRSA infection[16, 54]. AAC is an anti-MRSA antibody linked to an antibiotic using a protease-sensitive linker[55]. When MRSA is opsonized by the antibody and is phagocytized by immune cells, the linker is cleaved by host cell proteases, and the antibiotic is released close to the bacteria and in the compartment with antibiotic tolerant bacteria[55]. Optimized antibiotics, with superior potency, efficacy, and specificity, are more effective the antibiotics alone for the treatment of secondary MRSA infection[55]. Moreover, AAC can combat antibiotic-tolerant bacteria more effectively and can improve the permeability of antibiotics into host cells. However, high production costs hinder their clinical translation [56]. Antibiotic adjuvant (AA) is another strategy for developing novel antibiotics. To date, AAs mainly contain efflux pump inhibitors and β -lactamase inhibitors[16]. Efflux pumps can actively extrude antibiotics, increasing their minimum inhibitory concentration (MIC) or even losing their antimicrobial activity. Using efflux pumps as therapeutic targets, efflux pump inhibitors (EPIs) were developed. EPIs, with no antibacterial activity on their own, inhibit efflux pumps by interfering with efflux gene expression, adding functional groups to the drug substrate, and developing small-molecules as substrate analogues to hinder identification, or to interfere with the assembly of channel proteins [57]. EPIs can increase the activity of antibacterial drugs subject to efflux, maintain the drug concentration at the therapeutic dose and shorten the treatment duration[58]. However, its use requires high-dose administration, which could be toxic [16]. This high-dose administration makes it difficult to widely develop EPIs.β -Lactamase can deactivate antibiotics[16]. Thus, β -lactamases inhibitors (BLIs), capable of inactivating mostβ -lactamases, are a proper antibiotic adjuvant. These inhibitors are mainly used in treating G- bacterial infection, while their use in G+ bacteria still needs to be developed[59].
3.3 Vaccines
Vaccination to prevent MRSA infection acquisition is the main treatment strategy. Vaccination can decrease the occurrence and transmission of resistant strains [60]. Vaccines usually induce the immune system to react to multiple targets, which makes it more difficult for bacteria to evade the immune response induced by vaccination, namely, it restricts the mutation of bacterial resistance genes [61]. Vaccines do not increase antibiotic resistance, and most vaccines still work after long-term use. Moreover, vaccination can restrict the ability of bacteria to colonize and establish an infection by enhancing immunity [62]. However, these vaccines have had limited or no success in human trials[63, 64].