Molecular Mechanisms of Bacterial Resistance to Antimicrobial Peptides in the Modern Era: An Updated Review

Abstract

Antimicrobial resistance (AMR) poses a serious global health concern, resulting in a significant number of deaths annually due to infections that are resistant to treatment. Amidst this crisis, antimicrobial peptides (AMPs) have emerged as promising alternatives to conventional antibiotics (ATBs). These cationic peptides, naturally produced by all kingdoms of life, play a crucial role in the innate immune system of multicellular organisms and in bacterial interspecies competition by exhibiting broad-spectrum activity against bacteria, fungi, viruses, and parasites. AMPs target bacterial pathogens through multiple mechanisms, most importantly by disrupting their membranes, leading to cell lysis. However, bacterial resistance to host AMPs has emerged due to a slow co-evolutionary process between microorganisms and their hosts. Alarmingly, the development of resistance to last-resort AMPs in the treatment of MDR infections, such as colistin, is attributed to the misuse of this peptide and the high rate of horizontal genetic transfer of the corresponding resistance genes. AMP-resistant bacteria employ diverse mechanisms, including but not limited to proteolytic degradation, extracellular trapping and inactivation, active efflux, as well as complex modifications in bacterial cell wall and membrane structures. This review comprehensively examines all constitutive and inducible molecular resistance mechanisms to AMPs supported by experimental evidence described to date in bacterial pathogens. We also explore the specificity of these mechanisms toward structurally diverse AMPs to broaden and enhance their potential in developing and applying them as therapeutics for MDR bacteria. Additionally, we provide insights into the significance of AMP resistance within the context of host-pathogen interactions.

Keywords: antimicrobial peptides; antimicrobial resistance; bacterial membranes; cationic peptides; efflux pumps; host–pathogen interactions; lipopolysaccharides; molecular resistance; mutations; peptide modifications.

Figure 1

Advantages of AMPs over traditional antibiotics. This figure illustrates the differences between ATBs and AMPs regarding their target, resistance mechanisms, spectrum of activity, and cytotoxicity.

Figure 2

Classification of antimicrobial peptides. AMPs are classified according to seven criteria. The classification of AMPs based on their three-dimensional structure encompasses four categories: alpha (α), beta (β), alpha–beta (α-β), and non-α-β. These categories are defined by the presence of helical structures, β strands, a combination of helical and β structures, or the absence of both α and β structures, respectively. Regarding covalent bond classification, peptides are divided into four groups based on their polypeptide chain-bonding patterns: Class O peptides adopt circular structures due to a bond between the N-terminal and C-terminal backbone atoms; class P peptides take on a shape resembling the letter “P”, formed by a bond between the side chain of one amino acid and the backbone of another; class S peptides exhibit bonds between different side chains; and class L includes all linear peptides [11].

Figure 3

Modifications of LPS for enhanced resistance against AMPs. The position of a substituent or branch is identified by the number of the carbon atom it is bonded to.

Figure 4

Modifications of teichoic acids, lipoteichoic acids, and peptidoglycans associated with AMP resistance. Enzymes involved in the modification reaction are mentioned between parentheses.

Figure 5

Bacterial mechanisms of AMP resistance not associated with modifications of cell wall structures. (A): Active efflux. (B): Secreted proteinases degrading AMPs. (C): Surface proteins trapping/inhibiting AMPs. (D): Secreted proteins blocking/inhibiting AMPs. (E): Pili-mediated blocking of AMPs. (F): Capsule-mediated protection. (G): Modifications of cytoplasmic membrane phospholipids by the incorporation of cationic residues. (H): Transcriptional downregulation of AMP production by mucosal host cells.