Macolacin Antibiotic Analogs for mcr-1 Resistant Bacteria
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Solution Overview
Problem
The rise of multidrug-resistant gram-negative bacteria poses a significant threat to public health, with existing antibiotics like colistin becoming less effective against pathogens with resistance mechanisms such as mcr-1, necessitating the development of new compositions and methods for treating infections.
Innovation Solution
The discovery and synthesis of macolacins, which are compounds derived from bacterial natural products, including macolacin analogs, that exhibit antibacterial activity against multidrug-resistant pathogens, leveraging biosynthetic gene clusters and chemical modifications to enhance efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If colistin is used to treat MDR gram-negative infections, then therapeutic effect is achieved, but bacterial resistance (mcr-1) develops reducing efficacy
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of colistin to create macolacins with altered amino acid sequences and side chain configurations. These structural parameter changes enable the new compounds to bypass mcr-1 resistance mechanisms while maintaining antibacterial activity against MDR gram-negative pathogens.
Solution Approach 2:
The invention creates composite antibiotic structures by combining the core colistin framework with modified amino acid residues and side chain variations. This composite approach generates macolacin derivatives that possess both the original antimicrobial properties and enhanced resistance to mcr-1 mediated efflux pumps.
2Productivity
If bacterial natural products are used as antibiotic sources, then clinically useful antibiotics are discovered, but high rediscovery rates occur reducing productivity
Solution Approach 1:
The patent segments the colistin biosynthetic gene cluster into modular components (NRPS modules) that can be independently manipulated. This segmentation allows systematic modification of individual amino acid positions and side chains, enabling the generation of novel macolacin variants without rediscovering the original colistin structure.
Solution Approach 2:
The invention introduces dynamic variability into the antibiotic discovery process by using heterologous expression systems that can rapidly produce diverse macolacin analogs with different amino acid sequences. This dynamic approach replaces static natural product isolation with an adaptable biosynthetic platform that continuously generates new candidates.
3Reliability
If colistin is used as last line of defense, then MDR infections are treated, but resistance mechanisms like mcr-1 reduce therapeutic effectiveness
Solution Approach 1:
The patent converts the harm caused by mcr-1 resistance into a benefit by designing macolacins that specifically target the weakness of resistant bacteria. The modified structures exploit the fact that mcr-1 expressing bacteria have altered membrane properties, making them more susceptible to the enhanced membrane disruption capability of macolacins with modified amino acid side chains.
Data Source
AI summary
The present invention provides methods, compositions, and articles of manufacture useful for the prophylactic and therapeutic amelioration and treatment of gram-positive bacteria, and related conditions. The present invention provides compositions and methods incorporating and utilizing macolacin antibiotics or derivatives or variants thereof.