Resistance of Gram-Negative Bacteria to Current Antibacterial Agents and Approaches to Resolve It

Abstract

Antimicrobial resistance represents an enormous global health crisis and one of the most serious threats humans face today. Some bacterial strains have acquired resistance to nearly all antibiotics. Therefore, new antibacterial agents are crucially needed to overcome resistant bacteria. In 2017, the World Health Organization (WHO) has published a list of antibiotic-resistant priority pathogens, pathogens which present a great threat to humans and to which new antibiotics are urgently needed the list is categorized according to the urgency of need for new antibiotics as critical, high, and medium priority, in order to guide and promote research and development of new antibiotics. The majority of the WHO list is Gram-negative bacterial pathogens. Due to their distinctive structure, Gram-negative bacteria are more resistant than Gram-positive bacteria, and cause significant morbidity and mortality worldwide. Several strategies have been reported to fight and control resistant Gram-negative bacteria, like the development of antimicrobial auxiliary agents, structural modification of existing antibiotics, and research into and the study of chemical structures with new mechanisms of action and novel targets that resistant bacteria are sensitive to. Research efforts have been made to meet the urgent need for new treatments; some have succeeded to yield activity against resistant Gram-negative bacteria by deactivating the mechanism of resistance, like the action of the β-lactamase Inhibitor antibiotic adjuvants. Another promising trend was by referring to nature to develop naturally derived agents with antibacterial activity on novel targets, agents such as bacteriophages, DCAP(2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2(hydroxymethyl)propane1,3-diol, Odilorhabdins (ODLs), peptidic benzimidazoles, quorum sensing (QS) inhibitors, and metal-based antibacterial agents.

Keywords: Gram-negative; alternative therapies; antibiotic; antimicrobial; bacteria; multidrug resistance (MDR); pathogens; resistance.

Figure 1

WHO list of priority pathogens grouped under three priority categories according to their antibiotic resistance: Critical, high and medium to encourage research and development of new antibiotics.

Figure 2

A diagram describes the cell wall structure of Gram-negative bacteria.

Figure 3

Structure of Gram-negative bacteria and their mechanisms of resistance.

Figure 4

Chemical structures of clavulanic acid, salbactam, tazobactam, LN-1-255, DBOs core, relebactam, zidebactam, RPX7009, DCAP, peptidic benzimidazol, isobutyl-DPD and phenyl-DPD.