Critical analysis of antibacterial agents in clinical development

Abstract

| The antibacterial agents currently in clinical development are predominantly derivatives of well-established antibiotic classes and were selected to address the class-specific resistance mechanisms and determinants that were known at the time of their discovery. Many of these agents aim to target the antibiotic-resistant priority pathogens listed by the WHO, including Gram-negative bacteria in the critical priority category, such as carbapenem-resistant Acinetobacter, Pseudomonas and Enterobacterales. Although some current compounds in the pipeline have exhibited increased susceptibility rates in surveillance studies that depend on geography, pre-existing cross-resistance both within and across antibacterial classes limits the activity of many of the new agents against the most extensively drug-resistant (XDR) and pan-drug-resistant (PDR) Gram-negative pathogens. In particular, cross-resistance to unrelated classes may occur by co-selection of resistant strains, thus leading to the rapid emergence and subsequent spread of resistance. There is a continued need for innovation and new-class antibacterial agents in order to provide effective therapeutic options against infections specifically caused by XDR and PDR Gram-negative bacteria. ✉

Outer Membrane Disruption Overcomes Intrinsic, Acquired, and Spontaneous Antibiotic Resistance

“…Increasing the arsenal of available antibiotics is paramount to addressing the growing resistance crisis ( 1 , 2 ). Encouraging progress has been made in the treatment of Gram-positive pathogens ( 3 ), with two new antibiotic classes, cyclic lipopeptides (daptomycin) and oxazolidinones (linezolid), introduced within the last 20 years. Additionally, two novel Gram-positive active antibiotics are currently in clinical trials ( 3 ).…”

“…Encouraging progress has been made in the treatment of Gram-positive pathogens ( 3 ), with two new antibiotic classes, cyclic lipopeptides (daptomycin) and oxazolidinones (linezolid), introduced within the last 20 years. Additionally, two novel Gram-positive active antibiotics are currently in clinical trials ( 3 ). Unfortunately, antibiotic development for Gram-negative bacteria has remained stagnant.…”

“…Unfortunately, antibiotic development for Gram-negative bacteria has remained stagnant. The last novel class of Gram-negative active antibiotics, the quinolones, were introduced into the clinic over 50 years ago ( 4 ), and none are currently in the clinical pipeline ( 3 ).…”

Current Antibiotic Resistance Trends of Uropathogens in Central Europe: Survey from a Tertiary Hospital Urology Department 2011–2019

“…There are multiple reasons for this that are out of the scope of this paper (high cost of antibiotic development, availability of inexpensive generic antimicrobials, antibiotic stewardship reducing overall antibiotic use, and regulated use of new antibiotics to maintain their efficiency) [ 26 ]. The few antimicrobials under development are mostly derivatives of the major existing antibiotic classes (particularly beta-lactams, beta-lactamase inhibitors, and tetracyclines) and all exhibit some degree of pre-existing cross-resistance [ 27 ]. Antimicrobial agents with non-traditional therapeutic targets (virulence factors inactivators, inhibitors of adhesion and biofilm formation, monoclonal antibodies against bacterial exotoxins, quorum-sensing and other communication channels disrupting agents or those countering immune evasion) are being developed but not yet ready for clinical use [ 28 ].…”

Silver Nanomaterials for Wound Dressing Applications

“…The ratio between different biofilm and non-biofilm creating bacterial types in a wound is dependent on type and time of treatment [6]. Thus, because a variety of different bacterial species live in the wounds, there is a widely acknowledged need for new antibacterial agents to address the global increase in resistance [7]. The level of resistance, especially against traditional antibiotics (for example, methicillin-resistant Staphylococcus aureus [8], penicillin-resistant Enterococcus faecalis [9] or multiresistant Mycobacterium tuberculosis [10]) is still increasing, and the rising incidence of antimicrobial resistance among pathogenic bacteria is one of the greatest healthcare challenges facing humanity today [11].…”