Bacterial resistance to antibacterial agents: Mechanisms, control strategies, and implications for global health

Abstract

The spread of bacterial drug resistance has posed a severe threat to public health globally. Here, we cover bacterial resistance to current antibacterial drugs, including traditional herbal medicines, conventional antibiotics, and antimicrobial peptides. We summarize the influence of bacterial drug resistance on global health and its economic burden while highlighting the resistance mechanisms developed by bacteria. Based on the One Health concept, we propose 4A strategies to combat bacterial resistance, including prudent Application of antibacterial agents, Administration, Assays, and Alternatives to antibiotics. Finally, we identify several opportunities and unsolved questions warranting future exploration for combating bacterial resistance, such as predicting genetic bacterial resistance through the use of more effective techniques, surveying both genetic determinants of bacterial resistance and the transmission dynamics of antibiotic resistance genes (ARGs).

Keywords: Antibiotics; Antimicrobial peptides; Bacterial resistance; Global health; Mechanism of action; Strategies.

Fig. 1.

A brief profile of the evolution of bacterial resistance to current antibacterial agents. Of the large number of bacteria in the world, a fraction causes diseases in humans and animals, against which we need effective antibacterial agents. Some bacteria (such as the ESKAPE pathogens) are particularly resistant to antibiotics (Martin et al., 2015). These resistant bacteria and ARGs are rapidly disseminated in humans, animals, and the environment by direct or indirect contact with each other or with excreta, animal products, soil, and water contributing to the concept of One Health (Larsson and Flach, 2021; Rana et al., 1991). ARB: antibiotic-resistant bacteria. ARGs: antibiotic resistance genes. Black arrow: the spread of ARB and ARGs in humans, animals, and the environment. Gray arrow: effects of drugs on bacteria or bacterial infections in humans and animals.

Fig. 2.

Timeline for bacterial resistance to develop against current antibacterial agents. (A) Traditional herbal medicines. (B) Conventional antibiotics. (C) Next-generation AMPs. Defensins: phase IV; magainin: phase III; PG-1: phase II; LL-37: phase I and II; other AMPs: no data. Rightward arrow: timeline; upward arrow: drug discovery date; downward arrow: Year when drug resistance was first reported.

Fig. 3.

Phenotypes of bacterial resistance to antibacterial agents. Bacterial resistance includes intrinsic resistance (only vertically transferred, taxa-specific) and acquired resistance (vertically or horizontally transferred, taxa-nonspecific). Bacteria can transfer ARGs by horizontal gene transfer (HGT), i.e., conjugation, transformation, or transduction, and by vertical gene transfer (VGT) during genome replication and cell division. HGT is regarded as one of the major mechanisms of ARG transfer and is responsible for the abundance of ARGs. VGT can determine the prevalence of ARGs within a bacterial community (Rana et al., 1991; Pereira et al., 2004; Cox and Wright, 2013).

Fig. 4.

Bacterial mechanisms of resistance to current antibacterial agents. (A) Resistance mechanisms. Bacterial resistance mechanisms include activated efflux pumps, modified targets, degradation or modification of drugs, and decreased permeability to drugs. (B) Bacterial efflux pumps. In Gram-positive bacteria, efflux pumps (such as the ABC superfamily, MFS, and the MATE family) are related to resistance to a few antibiotics and AMPs. Efflux pumps of Gram-negative bacteria include the ABC superfamily, MFS, SMR, and the RND family (Russell et al., 1986; Gunn et al., 1998; Shafer et al., 1998; Saar-Dover et al., 2012; Warner et al., 2008; Wang et al., 2017a; Uddin et al., 2021). IM: inner membrane; OM: outer membrane.

Fig. 5.

The 4A strategies to counter drug resistance. Effective strategies are urgently needed to combat bacterial resistance, including the prudent use of antibacterial agents, advanced molecular techniques, stringent administration and the need for novel alternatives to antibiotics, such as efflux pump inhibitors, vaccines, bacteriophages, immunoglobulins, AMPs, untapped herbal medicines, and probiotics (Kern and de With, 2012).