Thinking Outside the Bug: Molecular Targets and Strategies to Overcome Antibiotic Resistance

Abstract

Since their discovery in the early 20th century, antibiotics have been used as the primary weapon against bacterial infections. Due to their prophylactic effect, they are also used as part of the cocktail of drugs given to treat complex diseases such as cancer or during surgery, in order to prevent infection. This has resulted in a decrease of mortality from infectious diseases and an increase in life expectancy in the last 100 years. However, as a consequence of administering antibiotics broadly to the population and sometimes misusing them, antibiotic-resistant bacteria have appeared. The emergence of resistant strains is a global health threat to humanity. Highly-resistant bacteria like Staphylococcus aureus (methicillin-resistant) or Enterococcus faecium (vancomycin-resistant) have led to complications in intensive care units, increasing medical costs and putting patient lives at risk. The appearance of these resistant strains together with the difficulty in finding new antimicrobials has alarmed the scientific community. Most of the strategies currently employed to develop new antibiotics point towards novel approaches for drug design based on prodrugs or rational design of new molecules. However, targeting crucial bacterial processes by these means will keep creating evolutionary pressure towards drug resistance. In this review, we discuss antibiotic resistance and new options for antibiotic discovery, focusing in particular on new alternatives aiming to disarm the bacteria or empower the host to avoid disease onset.

Keywords: antibiotic resistance; antimicrobial peptides and proteins; bacterial effectors; host–pathogen interactions; protein–protein interactions.

Figure 1

Vancomycin and vancomycin analog’s discovery timeline. Left side: antibiotic discovery and approval. Right side: appearance of resistance. Each color corresponds to a different antibiotic. The red box shows the last vancomycin analogs approved. Information about methicillin and linezolid is included in the timeline too as they are alternative treatment options available when vancomycin resistance occurs.

Figure 2

Pivampicillin (A) and sultamicillin (B) structures. A methylene group (in orange) binds ampicillin with pivalic acid or sulbactam, respectively. When pivampicillin and sultamicillin are processed in the body, ampicillin and pivalic acid/sulbactam are released at equal ratios.

Figure 3

Protein synthesis process. E (exit), P (peptidyl), and A (aminoacyl) correspond to the different sites where the tRNA moves during the elongation phase. Linezolid inhibits the initiation phase of protein synthesis, while other protein synthesis inhibitors interfere in the elongation phase.

Figure 4

Timeline for antibiotic discovery. Stages for antibiotic discovery and the different steps carried out in each one.

Figure 5

(A) Autoinducer production by bacterial. Once a threshold is reached, production of virulence factors, bioluminescence or other molecules takes place. (B,C) Gram-negative and Gram-positive quorum sensing mechanisms. In Gram-negative bacteria like Pseudomonas aeruginosa, the autoinducers freely diffuse into the cell and associate with their receptor. In Gram-positive bacteria like Staphylococcus aureus, the receptor is associated with the cell membrane and is phosphorylated upon external binding of the autoinducer.

Figure 6

S. aureus’s four groups of autoinducer peptides (AIPs) and their propeptide sequences. The orange residues play important roles in propeptide processing. The underlined residues form the AIPs.

Figure 7

LL-37 antibacterial effect involves multiple strategies. LL-37 causes lysis of the bacterial membrane, attracts immune cell to the infection site, promotes apoptosis in some tissues, and inhibits apoptosis in neutrophils.