Next-generation strategy for treating drug resistant bacteria: Antibiotic hybrids

Abstract

Resistance against nearly all antibiotics used clinically have been documented in bacteria. There is an ever-increasing danger caused by multidrug-resistant Gram-negative bacteria in both hospital and community settings. In Gram-negative bacteria, intrinsic resistance to currently available antibiotics is mainly due to overexpressed efflux pumps which are constitutively present and also presence of protective outer membrane. Combination therapy, i.e. , use of two or more antibiotics, was thought to be an effective strategy because it took advantage of the additive effects of multiple antimicrobial mechanisms, lower risk of resistance development and lower mortality and improved clinical outcome. However, none of the benefits were seen in in vivo studies. Antibiotic hybrids are being used to challenge the growing drug resistance threat and increase the usefulness of current antibiotic arsenal. Antibiotic hybrids are synthetic constructs of two molecules which are covalently linked. These could be two antibiotics or antibiotic with an adjuvant (efflux pump inhibitor, siderophore, etc. ) which increases the access of the antibiotics to the target. The concepts, developments and challenges in the future use of antibiotic hybrids are discussed here. Majority of the studies have been conducted on fluoroquinolones and aminoglycosides molecules. The antibiotic tobramycin has the property to enhance the action of antimicrobial agents against which the multidrug-resistant Gram-negative bacteria were earlier resistant, and thus potentiating the action of legacy antibiotics. Antibiotic hybrids may have a role as the silver bullet in Gram-negative bacteria to overcome drug resistance as well as extend the spectrum of existing antibiotics

Clinico-Microbiological Investigation on Fosfomycin and Tigecycline Resistant Gram-Negative Bacilli Isolated from Urinary Tract Infections: A Potential Resurgence

“…Preventing microbiota that causes vaginal, perineal, and anterior urethral infections was the most important reason for collecting urine specimens (13). Thus, in the present study, urine specimens were investigated, which were collected using the urethral catheterization and/or clean-catch techniques (14). Moreover, information on underlying diseases and demographic data were also collected using the medical records of patients.…”

Anti-biofilm Fe3O4@C18-[1,3,4]thiadiazolo[3,2-a]pyrimidin-4-ium-2-thiolate Derivative Core-shell Nanocoatings

“…Despite significant research progress in developing novel anti-infectious therapeutic and preventive strategies, infectious diseases treatment still remains a big challenge, primarily because of the emergence of microbial resistance to nearly all antibiotics used clinically [ 1 , 2 , 3 ]. The most threatening are those produced by the multiple drug-resistant (MDR) bugs that emerged in both hospitals and the community.…”

“…Among these, the thiadiazolopyrimidine fused systems are particularly interesting as mesoionic purine bases analogs. Otherwise, the [ 1 , 3 , 4 ]thiadiazolo [3,2- a ]pyrimidine core induces a broad spectrum of pharmacological activities, including antimicrobial [ 40 , 41 , 42 , 43 , 44 , 45 , 46 ] and antitumoral ones [ 47 , 48 , 49 , 50 , 51 , 52 ].…”

Design, Synthesis and Antimicrobial Evaluation of New Norfloxacin-Naphthoquinone Hybrid Molecules

“…Recently, both emerging pathogenic bacteria and antibiotics drugresistance have highlighted an urgent need to find new more effective and less toxic therapeutic molecules, although the wide known arsenal of drugs available to treat bacterial infections. In particular, the interest in hybrid antibacterial molecules is given by their potential ability to suppress drug resistance evolution better than monotherapy having a single-pharmacokinetic profile [3].…”

“…In vitro antimicrobial activities of precursors norfloxacin (1) and quinones(2)(3)(4), and hybrid molecules 5-7 as sodium salts, expressed in inhibition diameter.…”