Antibiotic resistance has become a global health crisis. Antibiotics are undoubtedly indispensable in the fight against bacteria and have saved the lives of millions of people (Uddin et al., 2021a). However, with the increasing use of antibiotics, bacteria have more opportunities to develop more complex drug resistance. In some cases, bacteria simultaneously develop resistance to multiple antibiotics, a phenomenon that greatly limits treatment options. The threat posed by untreatable drug-resistant bacteria has been imminent since the beginning of the 21st century (Akram, Imtiaz, Haq, & u., 2023).

Given this increasingly serious crisis, we need new antibiotics to address the challenges brought about by resistance as well as a discovery and development pipeline that can remain viable for a long time to address the gap between the availability of new antibiotics and the growing need to confront antibiotic resistance.

Drug discovery research has long focused almost exclusively on finding or designing highly selective drugs that act on a single target. Single-target drugs have been considered ideal antibiotics, with the argument that high target specificity equals fewer side effects. However, the development of antibiotics over the last few decades has shown that resistance to antibiotics with a specific single target develops too quickly to be sustainable (Gray & Wenzel, 2020). In fact, retrospective studies have found that antibiotics with great long-term clinical success rarely have a single specific target (Drlica et al., 2009; Peters, 2013; Sharifzadeh, Dempwolff, Kearns, & Carlson, 2020). Antibiotics that truly have a single target are typically known to lead to high resistance in microorganisms (Chopra, 2007). Candidate antibiotics with multiple targets, including resistant substances such as nanocomposites, can simultaneously modulate multiple links in the disease network system and have great potential to overcome or at least delay drug resistance (Domalaon, Idowu, Zhanel, & Schweizer, 2018; Gajdács, 2019; Kabir & Muth, 2022; Li et al., 2016; Mahdi, Yousefi, Jasim, & Salavati-Niasari, 2022; Yousefi, Alshamsi, Amiri, & Salavati-Niasari, 2021).

Although there have been many studies on the development of drugs to slow down the development of drug resistance, the reduction of bacterial resistance by multitarget antibacterial drugs has not been widely discussed and is rarely mentioned in the peer reviewed literature. Therefore, we need to make more efforts in this regard. We believe that the discovery and design of multitarget drugs is an effective strategy to delay the development of drug resistance. We are committed to revealing the potential of multitarget drugs as an effective strategy for slowing the development of resistance. We review the existing literature and present their findings, summarizing multitarget antimicrobial compounds with the potential to reduce resistance and highlighting the role that multitarget drugs may play in overcoming resistance. Furthermore, many currently marketed drugs are thought to derive therapeutic benefit by interacting with multiple targets, but most of these have been discovered serendipitously, making the rational discovery of multitarget drugs an emerging field. This review provides useful information and new ideas to overcome resistance and to expand the scope of existing antibiotics.