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].